IP-Star^® Compact Automated System

Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts
Sanchez A. et al.
Background/aim: Histone methylation status is required to control gene expression. H3K27me3 is an epigenetic tri-methylation modification to histone H3 controlled by the demethylase JMJD3. JMJD3 is dysregulated in a wide range of cancers and has been shown to control the expression of a specific growth-modulato...

CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells.
Bommi-Reddy A. et al.
Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach...

Comprehensive characterization of the epigenetic landscape in Multiple Myeloma
Elina Alaterre et al.
Background: Human multiple myeloma (MM) cell lines (HMCLs) have been widely used to understand themolecular processes that drive MM biology. Epigenetic modifications are involved in MM development,progression, and drug resistance. A comprehensive characterization of the epigenetic landscape of MM wouldadvance our un...

Comprehensive characterization of the epigenetic landscape in Multiple Myeloma
Alaterre, Elina and Ovejero, Sara and Herviou, Laurie and de Boussac, Hugues and Papadopoulos, Giorgio and Kulis, Marta and Boireau, Stéphanie and Robert, Nicolas and Requirand, Guilhem and Bruyer, Angélique and Cartron, Guillaume and Vincent, Laure and M
Background: Human multiple myeloma (MM) cell lines (HMCLs) have been widely used to understand the molecular processes that drive MM biology. Epigenetic modifications are involved in MM development, progression, and drug resistance. A comprehensive characterization of the epigenetic landscape of MM would advance our...

Rhesus macaques self-curing from a schistosome infection can displaycomplete immunity to challenge
Amaral MS et al.
The rhesus macaque provides a unique model of acquired immunity against schistosomes, which afflict \>200 million people worldwide. By monitoring bloodstream levels of parasite-gut-derived antigen, we show that from week 10 onwards an established infection with Schistosoma mansoni is cleared in an exponential man...

Histone deacetylase 4 deletion broadly affects cardiac epigeneticrepression and regulates transcriptional susceptibility via H3K9methylation.
Finke Daniel et al.
Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 h...

The insecticide permethrin induces transgenerational behavioral changeslinked to transcriptomic and epigenetic alterations in zebrafish (Daniorerio).
Blanc, Mélanie et al.
The pyrethroid insecticide permethrin is widely used for agricultural and domestic purposes. Previous data indicated that it acts as a developmental neurotoxicant and can induce transgenerational effects in non-target organisms. However, associated underlying mechanisms remain unclear. The aim of this study was to i...

Chromatin dysregulation associated with NSD1 mutation in head and necksquamous cell carcinoma.
Farhangdoost, Nargess et al.
Chromatin dysregulation has emerged as an important mechanism of oncogenesis. To develop targeted treatments, it is important to understand the transcriptomic consequences of mutations in chromatin modifier genes. Recently, mutations in the histone methyltransferase gene nuclear receptor binding SET domain protein 1...

A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia
L. Tottone at al.
Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia (T-ALL). Here, we identify a highly conserved distal enh...

Postoperative abdominal sepsis induces selective and persistent changes inCTCF binding within the MHC-II region of human monocytes.
Siegler B. et al.
BACKGROUND: Postoperative abdominal infections belong to the most common triggers of sepsis and septic shock in intensive care units worldwide. While monocytes play a central role in mediating the initial host response to infections, sepsis-induced immune dysregulation is characterized by a defective antigen present...

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
Chen C. et al.
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50\% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection...

EZH2 and KDM6B Expressions Are Associated with Specific EpigeneticSignatures during EMT in Non Small Cell Lung Carcinomas.
Lachat C. et al.
The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the hist...

H3K27M in Gliomas Causes a One-Step Decrease in H3K27 Methylation andReduced Spreading within the Constraints of H3K36 Methylation.
Harutyunyan, Ashot S and Chen, Haifen and Lu, Tianyuan and Horth, Cynthiaand Nikbakht, Hamid and Krug, Brian and Russo, Caterina and Bareke, Ericand Marchione, Dylan M and Coradin, Mariel and Garcia, Benjamin A andJabado, Nada and Majewski, Jacek
The discovery of H3K27M mutations in pediatric gliomas marked a new chapter in cancer epigenomics. Numerous studies have investigated the effect of this mutation on H3K27 trimethylation, but only recently have we started to realize its additional effects on the epigenome. Here, we use isogenic glioma H3K27M cell lin...

Digging Deeper into Breast Cancer Epigenetics: Insights from ChemicalInhibition of Histone Acetyltransferase TIP60 .
Idrissou, Mouhamed and Lebert, Andre and Boisnier, Tiphanie and Sanchez,Anna and Houfaf Khoufaf, Fatma Zohra and Penault-Llorca, Frédérique andBignon, Yves-Jean and Bernard-Gallon, Dominique
Breast cancer is often sporadic due to several factors. Among them, the deregulation of epigenetic proteins may be involved. TIP60 or KAT5 is an acetyltransferase that regulates gene transcription through the chromatin structure. This pleiotropic protein acts in several cellular pathways by acetylating proteins. RNA...

Super-enhancer switching drives a burst in gene expression at themitosis-to-meiosis transition.
Maezawa, So and Sakashita, Akihiko and Yukawa, Masashi and Chen, Xiaotingand Takahashi, Kazuki and Alavattam, Kris G and Nakata, Ippo and Weirauch,Matthew T and Barski, Artem and Namekawa, Satoshi H
Owing to bursts in the expression of thousands of germline-specific genes, the testis has the most diverse and complex transcriptome of all organs. By analyzing the male germline of mice, we demonstrate that the genome-wide reorganization of super-enhancers (SEs) drives bursts in germline gene expression after the m...

Epigenetic regulation of the lineage specificity of primary human dermallymphatic and blood vascular endothelial cells.
Tacconi, Carlotta and He, Yuliang and Ducoli, Luca and Detmar, Michael
Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vasc...

Human papillomavirus type 38 alters wild-type p53 activity to promote cellproliferation via the downregulation of integrin alpha 1 expression.
Romero-Medina, MC and Venuti, A and Melita, G and Robitaille, A andCeraolo, MG and Pacini, L and Sirand, C and Viarisio, D and Taverniti, Vand Gupta, P and Scalise, M and Indiveri, C and Accardi, R and Tommasino, M
Tumor suppressors can exert pro-proliferation functions in specific contexts. In the beta human papillomavirus type 38 (HPV38) experimental model, the viral proteins E6 and E7 promote accumulation of a wild-type (WT) p53 form in human keratinocytes (HKs), promoting cellular proliferation. Inactivation of p53 by diff...

Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development
Roels J, Kuchmiy A, De Decker M, et al.
The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC-sequencing and ChIPmentation on well-defined thymocyte subsets that represent the conti...

Measuring Histone Modifications in the Human Parasite Schistosoma mansoni
de Carvalho Augusto R, Roquis D, Al Picard M, Chaparro C, Cosseau C, Grunau C.
DNA-binding proteins play critical roles in many major processes such as development and sexual biology of Schistosoma mansoni and are important for the pathogenesis of schistosomiasis. Chromatin immunoprecipitation (ChIP) experiments followed by sequencing (ChIP-seq) are useful to characterize the association of ge...

2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer.
Blomme A, Ford CA, Mui E, Patel R, Ntala C, Jamieson LE, Planque M, McGregor GH, Peixoto P, Hervouet E, Nixon C, Salji M, Gaughan L, Markert E, Repiscak P, Sumpton D, Blanco GR, Lilla S, Kamphorst JJ, Graham D, Faulds K, MacKay GM, Fendt SM, Zanivan S, Le
Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors...

Genome-Wide DNA Methylation Profiling in Early Stage I Lung Adenocarcinoma Reveals Predictive Aberrant Methylation in the Promoter Region of the Long Noncoding RNA PLUT: An Exploratory Study.
Kim-Wanner SZ, Assenov Y, Nair MB, Weichenhan D, Benner A, Becker N, Landwehr K, Kuner R, Sültmann H, Esteller M, Koch I, Lindner M, Meister M, Thomas M, Bieg M, Klingmüller U, Schlesner M, Warth A, Brors B, Seifried E, Bönig H, Plass C, Risch A, Muley T
INTRODUCTION: Surgical procedure is the treatment of choice in early stage I lung adenocarcinoma. However, a considerable number of patients experience recurrence within the first 2 years after complete resection. Suitable prognostic biomarkers that identify patients at high risk of recurrence (who may probably bene...

Multi-omic analysis of gametogenesis reveals a novel signature at the promoters and distal enhancers of active genes.
Crespo M, Damont A, Blanco M, Lastrucci E, Kennani SE, Ialy-Radio C, Khattabi LE, Terrier S, Louwagie M, Kieffer-Jaquinod S, Hesse AM, Bruley C, Chantalat S, Govin J, Fenaille F, Battail C, Cocquet J, Pflieger D
Epigenetic regulation of gene expression is tightly controlled by the dynamic modification of histones by chemical groups, the diversity of which has largely expanded over the past decade with the discovery of lysine acylations, catalyzed from acyl-coenzymes A. We investigated the dynamics of lysine acetylation and ...

AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation.
Yukawa M, Jagannathan S, Vallabh S, Kartashov AV, Chen X, Weirauch MT, Barski A
Activation of T cells is dependent on the organized and timely opening and closing of chromatin. Herein, we identify AP-1 as the transcription factor that directs most of this remodeling. Chromatin accessibility profiling showed quick opening of closed chromatin in naive T cells within 5 h of activation. These newly...

SMaSH: Sample matching using SNPs in humans.
Westphal M, Frankhouser D, Sonzone C, Shields PG, Yan P, Bundschuh R
BACKGROUND: Inadvertent sample swaps are a real threat to data quality in any medium to large scale omics studies. While matches between samples from the same individual can in principle be identified from a few well characterized single nucleotide polymorphisms (SNPs), omics data types often only provide low to mod...

Functionally Annotating Regulatory Elements in the Equine Genome Using Histone Mark ChIP-Seq.
Kingsley NB, Kern C, Creppe C, Hales EN, Zhou H, Kalbfleisch TS, MacLeod JN, Petersen JL, Finno CJ, Bellone RR
One of the primary aims of the Functional Annotation of ANimal Genomes (FAANG) initiative is to characterize tissue-specific regulation within animal genomes. To this end, we used chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me...

Methionine metabolism in health and cancer: a nexus of diet and precisionmedicine.
Sanderson, Sydney M and Gao, Xia and Dai, Ziwei and Locasale, Jason W
Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer path...

Reactivation of super-enhancers by KLF4 in human Head and Neck Squamous Cell Carcinoma.
Tsompana M, Gluck C, Sethi I, Joshi I, Bard J, Nowak NJ, Sinha S, Buck MJ
Head and neck squamous cell carcinoma (HNSCC) is a disease of significant morbidity and mortality and rarely diagnosed in early stages. Despite extensive genetic and genomic characterization, targeted therapeutics and diagnostic markers of HNSCC are lacking due to the inherent heterogeneity and complexity of the dis...

The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.
Weinberg DN, Papillon-Cavanagh S, Chen H, Yue Y, Chen X, Rajagopalan KN, Horth C, McGuire JT, Xu X, Nikbakht H, Lemiesz AE, Marchione DM, Marunde MR, Meiners MJ, Cheek MA, Keogh MC, Bareke E, Djedid A, Harutyunyan AS, Jabado N, Garcia BA, Li H, Allis CD,
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting the critical role of DNA methylation in the ...

Human mitochondrial DNA is extensively methylated in a non-CpG context
Patil Vibha, Cuenin Cyrille, Chung Felicia, Aguilera Jesus R Rodriguez, Fernandez-Jimenez Nora, Romero-Garmendia Irati, Bilbao Jose Ramon, Cahais Vincent, Rothwell Joseph, Herceg Zdenko
Mitochondrial dysfunction plays critical roles in cancer development and related therapeutic response; however, exact molecular mechanisms remain unclear. Recently, alongside the discovery of mitochondrial-specific DNA methyltransferases, global and site-specific methylation of the mitochondrial genome has been desc...

Development and epigenetic plasticity of murine Müller glia.
Dvoriantchikova G, Seemungal RJ, Ivanov D
The ability to regenerate the entire retina and restore lost sight after injury is found in some species and relies mostly on the epigenetic plasticity of Müller glia. To understand the role of mammalian Müller glia as a source of progenitors for retinal regeneration, we investigated changes in gene expres...

Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.
Krug B, De Jay N, Harutyunyan AS, Deshmukh S, Marchione DM, Guilhamon P, Bertrand KC, Mikael LG, McConechy MK, Chen CCL, Khazaei S, Koncar RF, Agnihotri S, Faury D, Ellezam B, Weil AG, Ursini-Siegel J, De Carvalho DD, Dirks PB, Lewis PW, Salomoni P, Lupie
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K...

Guidelines for optimized gene knockout using CRISPR/Cas9
Campenhout CV et al.
CRISPR/Cas9 technology has evolved as the most powerful approach to generate genetic models both for fundamental and preclinical research. Despite its apparent simplicity, the outcome of a genome-editing experiment can be substantially impacted by technical parameters and biological considerations. Here, we present ...

Repression of Germline Genes in Somatic Tissues by H3K9 Dimethylation of Their Promoters.
Rechtsteiner A, Costello ME, Egelhofer TA, Garrigues JM, Strome S, Petrella LN
Repression of germline-promoting genes in somatic cells is critical for somatic development and function. To study how germline genes are repressed in somatic tissues, we analyzed key histone modifications in three synMuv B mutants, , , and -all of which display ectopic expression of germline genes in the soma. LIN-...

Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined.
Kaleviste E, Saare M, Leahy TR, Bondet V, Duffy D, Mogensen TH, Jørgensen SE, Nurm H, Ip W, Davies EG, Sauer S, Syvänen AC, Milani L, Peterson P, Kisand K
STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. How...

H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis.
Harutyunyan AS, Krug B, Chen H, Papillon-Cavanagh S, Zeinieh M, De Jay N, Deshmukh S, Chen CCL, Belle J, Mikael LG, Marchione DM, Li R, Nikbakht H, Hu B, Cagnone G, Cheung WA, Mohammadnia A, Bechet D, Faury D, McConechy MK, Pathania M, Jain SU, Ellezam B,
Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally d...

Genetic, Inflammatory, and Epithelial Cell Differentiation Factors Control Expression of Human Calpain-14.
Miller DE, Forney C, Rochman M, Cranert S, Habel J, Rymer J, Lynch A, Schroeder C, Lee J, Sauder A, Smith Q, Chawla M, Trimarchi MP, Lu X, Fjellman E, Brusilovsky M, Barski A, Waggoner S, Weirauch MT, Rothenberg ME, Kottyan LC
Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease resulting in eosinophilic esophageal inflammation. We recently found that EoE susceptibility is associated with genetic variants in the promoter of , a gene with reported esophagus-specific expression. is dynamically up-regulated as a function...

The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue.
Dvoriantchikova G, Seemungal RJ, Ivanov D
The epigenetic plasticity of amphibian retinal pigment epithelium (RPE) allows them to regenerate the entire retina, a trait known to be absent in mammals. In this study, we investigated the epigenetic plasticity of adult murine RPE to identify possible mechanisms that prevent mammalian RPE from regenerating retinal...

EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation.
Herviou L, Jourdan M, Martinez AM, Cavalli G, Moreaux J
Plasma cells (PCs) play a major role in the defense of the host organism against pathogens. We have shown that PC generation can be modeled using multi-step culture systems that reproduce the sequential cell differentiation occurring in vivo. Using this unique model, we investigated the role of EZH2 during PC differ...

Protocols for Genetic and Epigenetic Studies of Rare Diseases Affecting Dental Tissues.
Amorim BR, Dos Santos PAC, de Lima CL, Andia DC, Mazzeu JF, Acevedo AC
This chapter describes methods related to the diagnosis of genetic dental diseases. Based on the present knowledge, clinical phenotyping and next-generation sequencing techniques are discussed. Methods necessary for Sanger sequencing, multiplex ligation-dependent probe amplification, and epigenetic modification meth...

TIP60: an actor in acetylation of H3K4 and tumor development in breast cancer.
Judes G, Dubois L, Rifaï K, Idrissou M, Mishellany F, Pajon A, Besse S, Daures M, Degoul F, Bignon YJ, Penault-Llorca F, Bernard-Gallon D
AIM: The acetyltransferase TIP60 is reported to be downregulated in several cancers, in particular breast cancer, but the molecular mechanisms resulting from its alteration are still unclear. MATERIALS & METHODS: In breast tumors, H3K4ac enrichment and its link with TIP60 were evaluated by chromatin immunoprecip...

Caenorhabditis elegans sperm carry a histone-based epigenetic memory of both spermatogenesis and oogenesis.
Tabuchi TM, Rechtsteiner A, Jeffers TE, Egelhofer TA, Murphy CT, Strome S
Paternal contributions to epigenetic inheritance are not well understood. Paternal contributions via marked nucleosomes are particularly understudied, in part because sperm in some organisms replace the majority of nucleosome packaging with protamine packaging. Here we report that in Caenorhabditis elegans sperm, th...

PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs.
Herviou L, Kassambara A, Boireau S, Robert N, Requirand G, Müller-Tidow C, Vincent L, Seckinger A, Goldschmidt H, Cartron G, Hose D, Cavalli G, Moreaux J
BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance. METHODS: We ident...

Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter.
Lund RJ, Osmala M, Malonzo M, Lukkarinen M, Leino A, Salmi J, Vuorikoski S, Turunen R, Vuorinen T, Akdis C, Lähdesmäki H, Lahesmaa R, Jartti T
Children with rhinovirus-induced severe early wheezing have an increased risk of developing asthma later in life. The exact molecular mechanisms for this association are still mostly unknown. To identify potential changes in the transcriptional and epigenetic regulation in rhinovirus-associated atopic or nonatopic a...

SIRT1-dependent epigenetic regulation of H3 and H4 histone acetylation in human breast cancer
Khaldoun Rifaï et al.
Breast cancer is the most frequently diagnosed malignancy in women worldwide. It is well established that the complexity of carcinogenesis involves profound epigenetic deregulations that contribute to the tumorigenesis process. Deregulated H3 and H4 acetylated histone marks are amongst those alterations. Sirtuin-1 (...

An Integrated and Semiautomated Microscaled Approach to Profile Cis-Regulatory Elements by Histone Modification ChIP-Seq for Large-Scale Epigenetic Studies.
Youhanna Jankeel D, Cayford J, Schmiedel BJ, Vijayanand P, Seumois G.
Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) is the preferred approach to map histone modifications and identify cis-regulatory DNA elements throughout the genome. Multiple methods have been described to increase the efficiency of library preparation and to reduce hands-on time as well as costs. T...

Gene promoter and exon DNA methylation changes in colon cancer development - mRNA expression and tumor mutation alterations.
Molnár B, Galamb O, Péterfia B, Wichmann B, Csabai I, Bodor A, Kalmár A, Szigeti KA, Barták BK, Nagy ZB, Valcz G, Patai ÁV, Igaz P, Tulassay Z
BACKGROUND: DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expre...

An improved assembly and annotation of the melon (Cucumis melo L.) reference genome.
Ruggieri V, Alexiou KG, Morata J, Argyris J, Pujol M, Yano R, Nonaka S, Ezura H, Latrasse D, Boualem A, Benhamed M, Bendahmane A, Cigliano RA, Sanseverino W, Puigdomènech P, Casacuberta JM, Garcia-Mas J
We report an improved assembly (v3.6.1) of the melon (Cucumis melo L.) genome and a new genome annotation (v4.0). The optical mapping approach allowed correcting the order and the orientation of 21 previous scaffolds and permitted to correctly define the gap-size extension along the 12 pseudomolecules. A new compreh...

Reciprocal signalling by Notch-Collagen V-CALCR retains muscle stem cells in their niche.
Baghdadi MB, Castel D, Machado L, Fukada SI, Birk DE, Relaix F, Tajbakhsh S, Mourikis P
The cell microenvironment, which is critical for stem cell maintenance, contains both cellular and non-cellular components, including secreted growth factors and the extracellular matrix. Although Notch and other signalling pathways have previously been reported to regulate quiescence of stem cells, the co...

Insulin promoter in human pancreatic β cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism.
Jian X, Felsenfeld G
Both type 1 and type 2 diabetes involve a complex interplay between genetic, epigenetic, and environmental factors. Our laboratory has been interested in the physical interactions, in nuclei of human pancreatic β cells, between the insulin ( gene and other genes that are involved in insulin metabolism. We have ...

A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2.
Daures M, Idrissou M, Judes G, Rifaï K, Penault-Llorca F, Bignon YJ, Guy L, Bernard-Gallon D
Histone methylation is essential for gene expression control. Trimethylated lysine 27 of histone 3 (H3K27me3) is controlled by the balance between the activities of JMJD3 demethylase and EZH2 methyltransferase. This epigenetic mark has been shown to be deregulated in prostate cancer, and evidence shows H3K27me3 enri...

Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor.
Frampton D, Schwenzer H, Marino G, Butcher LM, Pollara G, Kriston-Vizi J, Venturini C, Austin R, de Castro KF, Ketteler R, Chain B, Goldstein RA, Weiss RA, Beck S, Fassati A
The canine transmissible venereal tumor (CTVT) is a clonally transmissible cancer that regresses spontaneously or after treatment with vincristine, but we know little about the regression mechanisms. We performed global transcriptional, methylation, and functional pathway analyses on serial biopsies of vincristine-t...

Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure
Singh G. et al.
Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influenc...

APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients
Jean-Louis Guéant et. al.
To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimu...

The histone code reader Spin1 controls skeletal muscle development
Greschik H. et al.
While several studies correlated increased expression of the histone code reader Spin1 with tumor formation or growth, little is known about physiological functions of the protein. We generated Spin1M5 mice with ablation of Spin1 in myoblast precursors using the Myf5-Cre deleter strain. Most Spin1M5 mice die shortly...

Saliva as a Blood Alternative for Genome-Wide DNA Methylation Profiling by Methylated DNA Immunoprecipitation (MeDIP) Sequencing
Staunstrup N.H. et al.
Background: Interrogation of DNA methylation profiles hold promise for improved diagnostics, as well as the delineation of the aetiology for common human diseases. However, as the primary tissue of the disease is often inaccessible without complicated and inconvenient interventions, there is an increasing interest i...

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D, Digiammarino EL, Hansen TM, Risi RM, Frey R, Manaves V, Shaw B, Algire M, Hessler P, Lam LT, Uziel T, Faivre E, Ferguson D, Buchanan FG, Martin RL, Torrent M, Chiang GG, Karukurichi K, Langston JW, Weine
The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancer...

BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis.
Valinciute G. et al.
BACKGROUND AND PURPOSE: Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibrob...

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism
Li N. et al.
Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted ...

FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy
Bolte C. et al.
FOXF1, a member of the forkhead box family of transcription factors, has been previously shown to be critical for lung development, homeostasis, and injury responses. However, the role of FOXF1 in lung regeneration is unknown. Herein, we performed partial pneumonectomy, a model of lung regeneration, in mice lacking ...

Chromosome contacts in activated T cells identify autoimmune disease candidate genes
Burren OS et al.
BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within 4 h, act...

Genome-wide screen for differentially methylated long noncoding RNAs identifies Esrp2 and lncRNA Esrp2-as regulated by enhancer DNA methylation with prognostic relevance for human breast cancer
Heilmann K, Toth R, Bossmann C, Klimo K, Plass C, Gerhauser C.
The majority of long noncoding RNAs (lncRNAs) is still poorly characterized with respect to function, interactions with protein-coding genes, and mechanisms that regulate their expression. As for protein-coding RNAs, epigenetic deregulation of lncRNA expression by alterations in DNA methylation might contribute to c...

Platelet function is modified by common sequence variation in megakaryocyte super enhancers
Petersen R. et al.
Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits usi...

TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors
Ancey P.B. et al.
Understanding the processes that govern liver progenitor cell differentiation has important implications for the design of strategies targeting chronic liver diseases, whereby regeneration of liver tissue is critical. Although DNA methylation (5mC) and hydroxymethylation (5hmC) are highly dynamic during early embryo...

Natural and induced loss of function mutations in SlMBP21 MADS-box gene led to jointless-2 phenotype in tomato
Roldan M.V.G. et al.
Abscission is the mechanism by which plants disconnect unfertilized flowers, ripe fruits, senescent or diseased organs from the plant. In tomato, pedicel abscission is an important agronomic factor that controls yield and post-harvest fruit quality. Two non-allelic mutations, jointless (j) and jointless-2 (j-2), con...

Performance of four modern whole genome amplification methods for copy number variant detection in single cells
Deleye L. et al.
Whole genome amplification (WGA) has become an invaluable tool to perform copy number variation (CNV) detection in single, or a limited number of cells. Unfortunately, current WGA methods introduce representation bias that limits the detection of small CNVs. New WGA methods have been introduced that might have the p...

DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats
Brocks D. et al.
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) an...

Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A
Halaburková A. et al.
Background Hypericin-mediated photodynamic therapy (HY-PDT) has recently captured increased attention as an alternative minimally invasive anticancer treatment, although cancer cells may acquire resistance. Therefore, combination treatments may be necessary to enhance HY-PDT efficacy. Histone deacetylase inhibi...

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia
Micol J.B. et al.
Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated i...

Evolutionary re-wiring of p63 and the epigenomic regulatory landscape in keratinocytes and its potential implications on species-specific gene expression and phenotypes
Sethi I. et al.
Although epidermal keratinocyte development and differentiation proceeds in similar fashion between humans and mice, evolutionary pressures have also wrought significant species-specific physiological differences. These differences between species could arise in part, by the rewiring of regulatory network due to cha...

DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes
Guha M. et al.
The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectod...

Global analysis of H3K27me3 as an epigenetic marker in prostate cancer progression
Ngollo M. et al.
BACKGROUND: H3K27me3 histone marks shape the inhibition of gene transcription. In prostate cancer, the deregulation of H3K27me3 marks might play a role in prostate tumor progression. METHODS: We investigated genome-wide H3K27me3 histone methylation profile using chromatin immunoprecipitation (ChIP) and 2X400K p...

Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.
Cheung W. et al.
BACKGROUND: The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigation...

Crebbp loss cooperates with Bcl2 over-expression to promote lymphoma in mice
Idoia García-Ramírez, Saber Tadros, Inés González-Herrero, Alberto Martín-Lorenzo, Guillermo Rodríguez-Hernández, Dalia Moore, Lucía Ruiz-Roca, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Keenan Hartert, Romain Duval, David Klinkebiel, Martin B
CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 over-expression to promote B-cell lymphoma. Through tra...

Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4
Castex J. et al.
Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide...

Rapid Recall Ability of Memory T cells is Encoded in their Epigenome
Barski A. et al.
Even though T-cell receptor (TCR) stimulation together with co-stimulation is sufficient for the activation of both naïve and memory T cells, the memory cells are capable of producing lineage specific cytokines much more rapidly than the naïve cells. The mechanisms behind this rapid recall response of the ...

Evaluating the Feasibility of DNA Methylation Analyses Using Long-Term Archived Brain Formalin-Fixed Paraffin-Embedded Samples
Bak S.T. et al.
We here characterize the usability of archival formalin-fixed paraffin-embedded (FFPE) brain tissue as a resource for genetic and DNA methylation analyses with potential relevance for brain-manifested diseases. We analyzed FFPE samples from The Brain Collection, Aarhus University Hospital Risskov, Denmark (AUBC), co...

Distinct and Shared Determinants of Cardiomyocyte Contractility in Multi-Lineage Competent Ethnically Diverse Human iPSCs
Tomov M.L. et al.
The realization of personalized medicine through human induced pluripotent stem cell (iPSC) technology can be advanced by transcriptomics, epigenomics, and bioinformatics that inform on genetic pathways directing tissue development and function. When possible, population diversity should be included in new studies a...

Genome-wide epigenomic profiling for biomarker discovery
Dirks R.A.M. et al.
A myriad of diseases is caused or characterized by alteration of epigenetic patterns, including changes in DNA methylation, post-translational histone modifications, or chromatin structure. These changes of the epigenome represent a highly interesting layer of information for disease stratification and for personali...

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells
Chen L. et al.
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, ...

RNA polymerase II promoter-proximal pausing in mammalian long non-coding genes
Bunch H et al.
Mammalian genomes encode a large number of non-coding RNAs (ncRNAs) that greatly exceed mRNA genes. While the physiological and pathological roles of ncRNAs have been increasingly understood, the mechanisms of regulation of ncRNA expression are less clear. Here, our genomic study has shown that a significant number ...

Epigenetic dynamics of monocyte-to-macrophage differentiation
Wallner S et al.
BACKGROUND: Monocyte-to-macrophage differentiation involves major biochemical and structural changes. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were differentiated in...

Genome-wide DNA methylation profiling with MeDIP-seq using archived dried blood spots
Nicklas H. Staunstrup et al.
Background In utero and early-life experienced environmental exposures are suggested to play an important role in many multifactorial diseases potentially mediated through lasting effects on the epigenome. As the epigenome in addition remains modifiable throughout life, identifying specific disease-relevant biomarke...

H3K4 acetylation, H3K9 acetylation and H3K27 methylation in breast tumor molecular subtypes
Judes G et al.
AIM: Here, we investigated how the St Gallen breast molecular subtypes displayed distinct histone H3 profiles. PATIENTS & METHODS: 192 breast tumors divided into five St Gallen molecular subtypes (luminal A, luminal B HER2-, luminal B HER2+, HER2+ and basal-like) were evaluated for their histone H3 modifica...

Characterization of the replication timing program of 6 human model cell lines
Hadjadj D et al.
During the S-phase, the DNA replication process is finely orchestrated and regulated by two programs: the spatial program that determines where replication will start in the genome (Cadoret et al. (2008 Oct 14), Cayrou et al. (2011 Sep), Picard et al. (2014 May 1) [1], [2], [3]), and the temporal program that determ...

H4K5 histone acetylation of BRG1 is associated with heroin administration rather than addiction
Xu L et al.
Diacetylmorphine hydrochloride (heroin) addiction is a chronic relapsing brain disorder that is a heavy public health burden worldwide. Brm/SWI2-related gene-1 (BRG1) is a tumor suppressor gene that can influence embryogenesis and the development of the cerebellum. The current study aimed to investigate the effect o...

Regulation of the DNA Methylation Landscape in Human Somatic Cell Reprogramming by the miR-29 Family
Hysolli E et al.
Reprogramming to pluripotency after overexpression of OCT4, SOX2, KLF4, and MYC is accompanied by global genomic and epigenomic changes. Histone modification and DNA methylation states in induced pluripotent stem cells (iPSCs) have been shown to be highly similar to embryonic stem cells (ESCs). However, epigenetic d...

Epigenetic Modifications with DZNep, NaBu and SAHA in Luminal and Mesenchymal-like Breast Cancer Subtype Cells
Dagdemir A et al.
BACKGROUND/AIM: Numerous studies have shown that breast cancer and epigenetic mechanisms have a very powerful interactive relation. The MCF7 cell line, representative of luminal subtype and the MDA-MB 231 cell line representative of mesenchymal-like subtype were treated respectively with a Histone Methyl Transferas...

Molecular and Epigenetic Biomarkers in Luminal Androgen Receptor: A Triple Negative Breast Cancer Subtype
Judes G et al.

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer.
Galamb O et al.
The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis i...

Genome-wide non-CpG methylation of the host genome during M. tuberculosis infection
Sharma G et al.
A mammalian cell utilizes DNA methylation to modulate gene expression in response to environmental changes during development and differentiation. Aberrant DNA methylation changes as a correlate to diseased states like cancer, neurodegenerative conditions and cardiovascular diseases have been documented. Here we sho...

Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis
Weigel C. et al.
Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation-induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences i...

Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling
Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P
In Graves' disease (GD), a combination of genetic, epigenetic and environmental factors causes an autoimmune response to the thyroid gland, characterized by lymphocytic infiltrations and autoantibodies targeting the thyroid stimulating hormone receptor (TSHR) and other thyroid antigens. To identify the epigenetic ch...

The Nuclear Ribonucleoprotein SmD1 Interplays with Splicing, RNA Quality Control, and Posttranscriptional Gene Silencing in Arabidopsis
Elvira-Matelot E. et al.
RNA quality control (RQC) eliminates aberrant RNAs based on their atypical structure, whereas posttranscriptional gene silencing (PTGS) eliminates both aberrant and functional RNAs through the sequence-specific action of short interfering RNAs (siRNAs). The Arabidopsis thaliana mutant smd1b was identified in a genet...

DNMT3L enables accumulation and inheritance of epimutations in transgenic Drosophila
Basu A et al.
DNMT3L is an important epigenetic regulator in mammals, integrating DNA methylation and histone modification based epigenetic circuits. Here we show DNMT3L to be a part of the machinery that enables inheritance of epigenetic modifications from one generation to the next. Ectopic expression of DNMT3L in Drosophila, w...

The chloroplastic DEVH-box RNA helicase INCREASED SIZE EXCLUSION LIMIT 2 involved in plasmodesmata regulation is required for group II intron splicing
Carlotto N, Wirth S, Furman N, Ferreyra Solari N, Ariel F, Crespi M, Kobayashi K
INCREASED SIZE EXCLUSION LIMIT 2 (ISE2) encodes a putative DEVH-box RNA helicase originally identified through a genetic screening for Arabidopsis mutants altered in plasmodesmata (PD) aperture. Depletion of ISE2 also affects chloroplasts activity, decreases accumulation of photosynthetic pigments and alters express...

Standardizing chromatin research: a simple and universal method for ChIP-seq
Laura Arrigoni, Andreas S. Richter, Emily Betancourt, Kerstin Bruder, Sarah Diehl, Thomas Manke and Ulrike Bönisch
Here we demonstrate that harmonization of ChIP-seq workflows across cell types and conditions is possible when obtaining chromatin from properly isolated nuclei. We established an ultrasound-based nuclei extraction method (Nuclei Extraction by Sonication) that is highly effective across various organisms, cell ...

A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice
Haljasorg U et al.
Autoimmune regulator (Aire) has a unique expression pattern in thymic medullary epithelial cells (mTECs), in which it plays a critical role in the activation of tissue-specific antigens. The expression of Aire in mTECs is activated by receptor activator of nuclear factor κB (RANK) signaling; however, the molec...

Progressive Chromatin Condensation and H3K9 Methylation Regulate the Differentiation of Embryonic and Hematopoietic Stem Cells
Ugarte F at al.
Epigenetic regulation serves as the basis for stem cell differentiation into distinct cell types, but it is unclear how global epigenetic changes are regulated during this process. Here, we tested the hypothesis that global chromatin organization affects the lineage potential of stem cells and that manipulation of c...

Loss of BAP1 function leads to EZH2-dependent transformation
LaFave ML et al.
The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here...

Transcription Factor Repertoire of Homeostatic Eosinophilopoiesis
Bouffi C, Kartashov AV, Schollaert KL, Chen X, Bacon WC, Weirauch MT, Barski A, Fulkerson PC
The production of mature eosinophils (Eos) is a tightly orchestrated process with the aim to sustain normal Eos levels in tissues while also maintaining low numbers of these complex and sensitive cells in the blood. To identify regulators of homeostatic eosinophilopoiesis in mice, we took a global approach to identi...

Comparative analysis of anti-viral transcriptomics reveals novel effects of influenza immune antagonism
Thakar J, Hartmann BM, Marjanovic N, Sealfon SC, Kleinstein SH
BACKGROUND: Comparative analysis of genome-wide expression profiles are increasingly being used to study virus-specific host interactions. In order to gain mechanistic insights, gene expression profiles can be combined with information on DNA-binding sites of transcription factors to detect transcription factor a...

The interaction of mycobacterial protein Rv2966c with host chromatin is mediated through non-CpG methylation and histone H3/H4 binding.
Sharma G, Upadhyay S, Srilalitha M, Nandicoori VK, Khosla S
To effectively modulate the gene expression within an infected mammalian cell, the pathogen Mycobacterium tuberculosis would need to bring about epigenetic modifications at appropriate genomic loci. Working on this hypothesis, we show in this study that the mycobacterial protein Rv2966c is a 5-methylcytosine-specifi...

An automated method for efficient, accurate and reproducible construction of RNA-seq libraries.
Tsompana M, Valiyaparambil S, Bard J, Marzullo B, Nowak N, Buck MJ
BACKGROUND: Integration of RNA-seq expression data with knowledge on chromatin accessibility, histone modifications, DNA methylation, and transcription factor binding has been instrumental for the unveiling of cell-specific local and long-range regulatory patterns, facilitating further investigation on the underlyin...

Bacterial Infection Remodels the DNA Methylation Landscape of Human Dendritic Cells
Pacis A, Tailleux L, Lambourne J, Yotova V, Dumaine A, Danckaert A, Luca F, Grenier JC, Hansen K, Gicquel B, Yu M, Pai A, Tung J, He C, Pastinen T, Pique-Regi R, Gilad Y, Barreiro L
DNA methylation is thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a pathogenic bacteria is associated with rapid changes in methylation at thousands of loci. Infection-induced changes in m...

The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer.
Wade MA, Jones D, Wilson L, Stockley J, Coffey K, Robson CN, Gaughan L
Endocrine therapy has successfully been used to treat estrogen receptor (ER)-positive breast cancer, but this invariably fails with cancers becoming refractory to treatment. Emerging evidence has suggested that fluctuations in ER co-regulatory protein expression may facilitate resistance to therapy and be involved i...

A Novel Role for Kruppel-like Factor 14 (KLF14) in T-Regulatory Cell Differentiation
Sarmento OF, Svingen PA, Xiong Y, Xavier RJ, McGovern D, Smyrk TC, Papadakis K, Urrutia RA, Faubion WA
Background & Aims Kruppel-like Factor 14 (KLF14) proteins function as epigenetic reprogramming factors during cell differentiation in many cell populations and in engineered induced pluripotent stem cells. In this study, we determined the function of KLF14 in the regulation of forkhead box protein 3 (FOXP3), a t...

Polycomb Repressive Complex 2 Regulates Lineage Fidelity during Embryonic Stem Cell Differentiation.
Thornton SR, Butty VL, Levine SS, Boyer LA
Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation (H3K27me3), an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to pro...

Automating ChIP-seq Experiments to Generate Epigenetic Profiles on 10,000 HeLa Cells.
Berguet G, Hendrickx J, Sabatel C, Laczik M, Squazzo S, Mazon Pelaez I, Saxena R, Pendeville H, Poncelet D
Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) is a technique of choice for studying protein-DNA interactions. ChIP-seq has been used for mapping protein-DNA interactions and allocating histones modifications. The procedure is tedious and time consuming, and one of the major limitati...

Long noncoding RNA modulates alternative splicing regulators in Arabidopsis.
Bardou F, Ariel F, Simpson CG, Romero-Barrios N, Laporte P, Balzergue S, Brown JW, Crespi M
Alternative splicing (AS) of pre-mRNA represents a major mechanism underlying increased transcriptome and proteome complexity. Here, we show that the nuclear speckle RNA-binding protein (NSR) and the AS competitor long noncoding RNA (or ASCO-lncRNA) constitute an AS regulatory module. AtNSR-GFP translational fusions...

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.
Kottyan LC, Davis BP, Sherrill JD, Liu K, Rochman M, Kaufman K, Weirauch MT, Vaughn S, Lazaro S, Rupert AM, Kohram M, Stucke EM, Kemme KA, Magnusen A, He H, Dexheimer P, Chehade M, Wood RA, Pesek RD, Vickery BP, Fleischer DM, Lindbad R, Sampson HA, Mukkad
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating asso...

Noncoding Transcription by Alternative RNA Polymerases Dynamically Regulates an Auxin-Driven Chromatin Loop.
Ariel F, Jegu T, Latrasse D, Romero-Barrios N, Christ A, Benhamed M, Crespi M
The eukaryotic epigenome is shaped by the genome topology in three-dimensional space. Dynamic reversible variations in this epigenome structure directly influence the transcriptional responses to developmental cues. Here, we show that the Arabidopsis long intergenic noncoding RNA (lincRNA) APOLO is transcribed by RN...

Two CCAAT box-binding transcription factors redundantly regulate early steps of the legume-rhizobia endosymbiosis.
Laloum T, Baudin M, Frances L, Lepage A, Billault-Penneteau B, Cerri MR, Ariel F, Jardinaud MF, Gamas P, de Carvalho-Niebel F, Niebel A
During endosymbiotic interactions between legume plants and nitrogen-fixing rhizobia, successful root infection by bacteria and nodule organogenesis requires the perception and transduction of bacterial lipo-chitooligosaccharidic signal called Nod Factor (NF). NF perception in legume roots leads to the activation of...

Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia.
Sonnet M, Claus R, Becker N, Zucknick M, Petersen J, Lipka DB, Oakes CC, Andrulis M, Lier A, Milsom MD, Witte T, Gu L, Kim-Wanner SZ, Schirmacher P, Wulfert M, Gattermann N, Lübbert M, Rosenbauer F, Rehli M, Bullinger L, Weichenhan D, Plass C
BACKGROUND: Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. METHODS: We screened genome-wide fo...

Stable methylation at promoters distinguishes Epiblast Stem Cells from Embryonic Stem Cells and the in vivo epiblast.
Veillard AC, Marks H, Bernardo AS, Jouneau L, Laloe D, Boulanger L, Kaan A, Brochard V, Tosolini M, Pedersen R, Stunnenberg H, Jouneau A.
Embryonic Stem Cells (ESCs) and Epiblast Stem Cells (EpiSCs) are the in vitro representatives of naïve and primed pluripotency, respectively. It is currently unclear how their epigenomes underpin the phenotypic and molecular characteristics of these distinct pluripotent states. Here, we performed a genome-wide ...

MBD4 cooperates with DNMT1 to mediate methyl-DNA repression and protects mammalian cells from oxidative stress.
Laget S, Miotto B, Chin HG, Estève PO, Roberts RJ, Pradhan S, Defossez PA
Oxidative stress induces genome-wide remodeling of the chromatin structure. In this study, we identify Methyl-CpG Binding Protein 4 (MBD4), a multifunctional enzyme involved in DNA demethylation, base excision repair, and gene expression regulation, as an essential factor in response to oxidative stress. We provide ...

Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.
Wilson GA, Butcher LM, Foster HR, Feber A, Roos C, Walter L, Woszczek G, Beck S, Bell CG
BACKGROUND: Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment's influence on the epigenome, and therefore genome function, as well as conversely the genome's facilitative effect on the epigenome, analysis of this level of regu...

Demethylation of the human eotaxin-3 gene promoter leads to the elevated expression of eotaxin-3.
Lim E, Rothenberg ME
DNA demethylation has been primarily studied in the context of development biology, cell fate, and cancer, with less attention on inflammation. In this article, we investigate the association between DNA methylation and production of the chemoattractant cytokine eotaxin-3 in the tissue of patients with allergic dise...

Differential methylation of the TRPA1 promoter in pain sensitivity.
Bell JT, Loomis AK, Butcher LM, Gao F, Zhang B, Hyde CL, Sun J, Wu H, Ward K, Harris J, Scollen S, Davies MN, Schalkwyk LC, Mill J, , Williams FM, Li N, Deloukas P, Beck S, McMahon SB, Wang J, John SL, Spector TD
Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole-blood DNA methylation was characterized a...

Toxoplasma gondii inhibits IFN-γ- and IFN-β-induced host cell STAT1 transcriptional activity by increasing the association of STAT1 with DNA.
Rosowski EE, Nguyen QP, Camejo A, Spooner E, Saeij JP
The IFN-γ response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogen Toxoplasma gondii, but prior infection with Toxoplasma can inhibit this response. Recently it was reported that the Toxoplasma type II NTE strain prevents the recruitment of chromatin ...

Reactive Oxygen Species Induce Epigenetic Instability through the Formation of 8-Hydroxydeoxyguanosine in Human Hepatocarcinogenesis.
Nishida N, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Kudo M
Chronic hepatitis C (CHC) triggers oxidative stress and contributes to the emergence of hepatocellular carcinoma (HCC). We previously reported that tumor suppressor gene (TSG) methylation is a critical factor during the early stages of hepatocarcinogenesis. In this study, we clarify the association between oxidative...

Lack of decorin expression by human bladder cancer cells offers new tools in the therapy of urothelial malignancies.
Sainio A, Nyman M, Lund R, Vuorikoski S, Boström P, Laato M, Boström PJ, Järveläinen H
Decorin, a multifunctional small leucine-rich extracellular matrix proteoglycan, has been shown to possess potent antitumour activity. However, there is some uncertainty whether different cancer cells express decorin in addition to non-malignant stromal cells. In this study we clarified decorin expression by human b...

DNA methylation analysis of murine hematopoietic side population cells during aging.
Taiwo O, Wilson GA, Emmett W, Morris T, Bonnet D, Schuster E, Adejumo T, Beck S, Pearce DJ.
Stem cells have been found in most tissues/organs. These somatic stem cells produce replacements for lost and damaged cells, and it is not completely understood how this regenerative capacity becomes diminished during aging. To study the possible involvement of epigenetic changes in somatic stem cell aging, we used ...

Global alterations of DNA methylation in cholangiocarcinoma targets the Wnt signaling pathway
Goeppert B, Konermann C, Schmidt CR, Bogatyrova O, Geiselhart L, Ernst C, Gu L, Becker N, Zucknick M, Mehrabi A, Hafezi M, Klauschen F, Stenzinger A, Warth A, Breuhahn K, Renner M, Weichert W, Schirmacher P, Plass C, Weichenhan D
The molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We p...

Integrated virus-host methylome analysis in head and neck squamous cell carcinoma
Wilson GA, Lechner M, Köferle A, Caren H, Butcher LM, Feber A, Fenton T, Jay A, Boshoff C, Beck S
One in six cancers worldwide is caused by infection and human papillomavirus (HPV) is one of the main culprits. To better understand the dynamics of HPV integration and its effect on both the viral and host methylomes, we conducted whole-genome DNA methylation analysis using MeDIP-seq of HPV+ and HPV- head and neck ...

Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2.
Guilhamon P, Eskandarpour M, Halai D, Wilson GA, Feber A, Teschendorff AE, Gomez V, Hergovich A, Tirabosco R, Fernanda Amary M, Baumhoer D, Jundt G, Ross MT, Flanagan AM, Beck S
Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in t...

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas.
Kostareli E, Holzinger D, Bogatyrova O, Hielscher T, Wichmann G, Keck M, Lahrmann B, Grabe N, Flechtenmacher C, Schmidt CR, Seiwert T, Dyckhoff G, Dietz A, Höfler D, Pawlita M, Benner A, Bosch FX, Plinkert P, Plass C, Weichenhan D, Hess J
High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms ...

SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state.
Lodato MA, Ng CW, Wamstad JA, Cheng AW, Thai KK, Fraenkel E, Jaenisch R, Boyer LA
SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of ge...

Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma.
Lechner M, Fenton T, West J, Wilson G, Feber A, Henderson S, Thirlwell C, Dibra HK, Jay A, Butcher L, Chakravarthy AR, Gratrix F, Patel N, Vaz F, O'Flynn P, Kalavrezos N, Teschendorff AE, Boshoff C, Beck S
BACKGROUND: Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) represents a distinct clinical and epidemiological condition compared with HPV-negative (HPV-) HNSCC. To test the possible involvement of epigenetic modulation by HPV in HNSCC, we conducted a genome-wide DNA-methylation an...

Linking proteomic and transcriptional data through the interactome and epigenome reveals a map of oncogene-induced signaling.
Huang SS, Clarke DC, Gosline SJ, Labadorf A, Chouinard CR, Gordon W, Lauffenburger DA, Fraenkel E
Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections bet...

Histone lysine trimethylation or acetylation can be modulated by phytoestrogen, estrogen or anti-HDAC in breast cancer cell lines.
Dagdemir A, Durif J, Ngollo M, Bignon YJ, Bernard-Gallon D
AIM: The isoflavones genistein, daidzein and equol (daidzein metabolite) have been reported to interact with epigenetic modifications, specifically hypermethylation of tumor suppressor genes. The objective of this study was to analyze and understand the mechanisms by which phytoestrogens act on chromatin in breast c...

Nano-MeDIP-seq: Methylome analysis using low DNA concentrations (Prot 58)
Taiwo O, Wilsona GA, Morris T, Seisenberger S, Reik W, Pearce D, Beck S, Butcher LM
To understand the functional consequences of DNA methylation on phenotypic plasticity, a genome - wide analysis should be embraced. This in turn requires a technique that balances accuracy, genome coverage, resolution and cost, yet is low in DNA input to minimise the drain on precious samples. MeDIP-seq fulfils thes...

Comparative genome-wide DNA methylation analysis of colorectal tumor and matched normal tissues
Simmer F, Brinkman AB, Assenov Y, Matarese F, Kaan A, Sabatino L, Villanueva A, Huertas D, Esteller M, Lengauer T, Bock C, Colantuoni V, Altucci L, Stunnenberg HG.
Aberrant DNA methylation often occurs in colorectal cancer (CRC). In our study we applied a genome-wide DNA methylation analysis approach, MethylCap-seq, to map the differentially methylated regions (DMRs) in 24 tumors and matched normal colon samples. In total, 2687 frequently hypermethylated and 468 frequently hyp...

HMGA1 Reprograms Somatic Cells into Pluripotent Stem Cells by Inducing Stem Cell Transcriptional Networks.
Shah SN, Kerr C, Cope L, Zambidis E, Liu C, Hillion J, Belton A, Huso DL, Resar LM
BACKGROUND: Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-l...

Human-specific CpG "beacons" identify loci associated with human-specific traits and disease.
Bell CG, Wilson GA, Butcher LM, Roos C, Walter L, Beck S
Regulatory change has long been hypothesized to drive the delineation of the human phenotype from other closely related primates. Here we provide evidence that CpG dinucleotides play a special role in this process. CpGs enable epigenome variability via DNA methylation, and this epigenetic mark functions as a regulat...

ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia.
Martens JH, Mandoli A, Simmer F, Wierenga BJ, Saeed S, Singh AA, Altucci L, Vellenga E, Stunnenberg HG
ERG and FLI1 are closely related members of the ETS family of transcription factors and have been identified as essential factors for the function and maintenance of normal hematopoietic stem cells. Here, genome-wide analysis revealed that both ERG and FLI1 occupy similar genomic regions as AML1-ETO in t(8;21) AMLs ...

Extensive promoter hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia.
Baer C, Claus R, Frenzel LP, Zucknick M, Park YJ, Gu L, Weichenhan D, Fischer M, Pallasch CP, Herpel E, Rehli M, Byrd JC, Wendtner CM, Plass C
Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and e...

High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation.
Wu AR, Kawahara TL, Rapicavoli NA, Riggelen JV, Shroff EH, Xu L, Felsher DW, Chang HY, Quake SR
Chromatin immunoprecipitation (ChIP) is an assay for interrogating protein-DNA interactions that is increasingly being used for drug target discovery and screening applications. Currently the complexity of the protocol and the amount of hands-on time required for this assay limits its use to low throughput applicati...

Methylome analysis using MeDIP-seq with low DNA concentrations.
Taiwo O, Wilson GA, Morris T, Seisenberger S, Reik W, Pearce D, Beck S, Butcher LM
DNA methylation is an epigenetic mark that has a crucial role in many biological processes. To understand the functional consequences of DNA methylation on phenotypic plasticity, a genome-wide analysis should be embraced. This in turn requires a technique that balances accuracy, genome coverage, resolution and cost,...

Quality control and single nucleotide resolution analysis of methylated DNA immunoprecipitation products.
Sengenès J, Daunay A, Charles MA, Tost J
DNA methylation patterns are altered in many diseases, and their analysis has become of great interest. Methylated DNA immunoprecipitation (MeDIP) is a simple method to enrich the methylated fraction of the genome. However, it has been difficult to assess the quality and the detailed methylation patterns of the immu...

Whole-genome DNA methylation profiling using MethylCap-seq.
Brinkman AB, Simmer F, Ma K, Kaan A, Zhu J, Stunnenberg HG
MethylCap-seq is a robust procedure for genome-wide profiling of DNA methylation. The approach consists of the capture of methylated DNA using the MBD domain of MeCP2, and subsequent next-generation sequencing of eluted DNA. Elution of the captured methylated DNA is done in steps using a salt gradient, which stratif...

AutoMeDIP-seq: A high-throughput, whole genome, DNA methylation assay
Butcher LM, Beck S
DNA methylation is an epigenetic mark linking DNA sequence and transcription regulation, and therefore plays an important role in phenotypic plasticity. The ideal whole genome methylation (methylome) assay should be accurate, affordable, high-throughput and agnostic with respect to genomic features. To this end, the...

A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice
Haljasorg U, Bichele R, Saare M, Guha M, Maslovskaja J, Kõnd K, Remm A, Pihlap M, Tomson L, Kisand K, Laan M, Peterson P
Autoimmune regulator (AIRE) has a unique expression pattern in thymic medullary epithelial cells (mTECs), in which it plays a critical role in the activation of tissue-specific antigens. The expression of Aire in mTECs is activated by RANK signaling; however, the molecular mechanism behind this activation is unknown...

Using ChIP-Seq Technology to Generate High-Resolution Profiles of Histone Modifications
O’Geen H, Echipare L, Farnham PJ
The dynamic modification of DNA and histones plays a key role in transcriptional regulation through - altering the packaging of DNA and modifying the nucleosome surface. These chromatin states, also referred to as the epigenome, are distinctive for different tissues, developmental stages, and disease states and can ...