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| Open AccessPolycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms
The role of Polycomb Repressive Complex 1 (PRC1) is well described in development. Here, the authors investigate canonical PRC1’s regulation of transcriptional programs in breast cancer where, in addition to its repressive function, it is also recruited to oncogenic active enhancers to regulate enhancer activity and chromatin accessibility.
- Ho Lam Chan
- , Felipe Beckedorff
- & Lluis Morey
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Article
| Open AccessJMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML
Histone demethylase JMJD3 is known to be oncogenic in preleukemic states and T-cell acute lymphocytic leukemia. Here, the authors show that in some acute myeloid leukemia subsets, JMJD3 can actually act as a potential oncorepressor via mediation of C/EBPβ-centered transcriptional programming.
- Shan-He Yu
- , Kang-Yong Zhu
- & Jiang Zhu
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Article
| Open AccessLTR retrotransposons transcribed in oocytes drive species-specific and heritable changes in DNA methylation
De novo DNA methylation during mouse oogenesis occurs within transcribed regions. Here the authors investigate the role of species-specific long terminal repeats (LTRs)-initiated transcription units in regulating the oocyte methylome, identifying syntenic regions in mouse, rat and human with divergent DNA methylation associated with private LITs.
- Julie Brind’Amour
- , Hisato Kobayashi
- & Matthew C. Lorincz
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Article
| Open AccessEpigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy
Immunoglobulin E (IgE)-mediated food allergy is a major issue that affects 2–10% of infants. Here the authors study the epigenetic regulation of the naive CD4+ T cell activation response among children with IgE-mediated food allergy finding epigenetic dysregulation in the early stages of signal transduction through the T cell receptor complex.
- David Martino
- , Melanie Neeland
- & Richard Saffery
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Article
| Open AccessHigh-resolution visualization of H3 variants during replication reveals their controlled recycling
Epigenetic modifications are a key contributor to cell identity, and their propagation is crucial for proper development. Here the authors use a super-resolution microscopy approach to reveal how histone variants are faithfully transmitted during genome duplication, and reveal an important role for the histone chaperone ASF1 in the redistribution of parental histones.
- Camille Clément
- , Guillermo A. Orsi
- & Geneviève Almouzni
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Comment
| Open AccessA critical view on transgenerational epigenetic inheritance in humans
- Bernhard Horsthemke
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Article
| Open AccessEpigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by aggregation of Tau, encoded by MAPT. Here, the authors perform an EWAS for PSP in prefrontal lobe tissue and find hypermethylation of DLX1 and its antisense transcript DLX1AS to associate with MAPT expression.
- Axel Weber
- , Sigrid C. Schwarz
- & Ulrich Müller
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Article
| Open AccessPRMT5-mediated regulation of developmental myelination
Myelin-forming cells derive from oligodendrocyte progenitors. Here the authors identify histone arginine methyl-transferase PRMT5 as critical for developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation, to favor differentiation.
- Antonella Scaglione
- , Julia Patzig
- & Patrizia Casaccia
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Article
| Open AccessNucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells
Genomic imprinting restricts transcription to predominantly one parental allele. Here the authors perform a screen for epigenetic factors involved in paternal allelic silencing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells and characterize a role for specific nucleoporins in mediating Kcnq1ot1 imprinted regulation.
- Saqib S. Sachani
- , Lauren S. Landschoot
- & Mellissa R. W. Mann
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Article
| Open AccessMutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis
ASXL1 gene is often mutated in myeloid malignancies. Here, the authors show that mutant ASXL1 and BAP1 are in a positive feedback loop such that BAP1 induces monoubiquitination of mutant ASXL1, which in turn enhances BAP1 activity to potentiate myeloid transformation via HOXA clusters and IRF8.
- Shuhei Asada
- , Susumu Goyama
- & Toshio Kitamura
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Article
| Open AccessUhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a
Uhrf1 is a known regulator of heterochromatin and DNA methylation in embryonic stem cells (ESCs). Here, the authors demonstrate that Uhrf1 acts together with the Set1/COMPASS complex regulator of active transcription to promote H3K4 methylation at bivalent loci and Uhrf1 loss results in disruption of differentiation.
- Kun-Yong Kim
- , Yoshiaki Tanaka
- & In-Hyun Park
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Article
| Open AccessPlacental H3K27me3 establishes female resilience to prenatal insults
Sex differences in placental O-linked N-acetylglucosamine transferase (OGT) activity mediate the effects of prenatal stress on neurodevelopmental programming. Here authors provide evidence that OGT confers variation in vulnerability to prenatal insults by establishing sex-specific trophoblast gene expression via regulation of H3K27me3.
- Bridget M. Nugent
- , Carly M. O’Donnell
- & Tracy L. Bale
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Article
| Open AccessAnalysis of sensitive information leakage in functional genomics signal profiles through genomic deletions
Functional genomics data from many studies are widely shared publicly for their value in biomedical and disease research. Here, the authors show sensitive information leakage is possible by analyzing functional genomics signal profiles, and develop an anonymization procedure for privacy protection.
- Arif Harmanci
- & Mark Gerstein
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Article
| Open AccessDual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL
Histone mark reader proteins bind to particular histone modifications and regulate chromatin state. Here, Qian et al. show that the SHORT LIFE reader has a unique ability to recognize both activating and repressive histone marks and that these interactions enable SHORT LIFE to repress flowering in plants.
- Shuiming Qian
- , Xinchen Lv
- & Jiamu Du
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Article
| Open AccessUnsupervised clustering and epigenetic classification of single cells
Single cell ATAC-seq (scATAC-seq) data reveals cellular level epigenetic heterogeneity but its application in delineating distinct subpopulations is still challenging. Here, the authors develop scABC, a statistical method for unsupervised clustering of scATAC-seq data and identification of open chromatin regions specific to cell identity.
- Mahdi Zamanighomi
- , Zhixiang Lin
- & Wing Hung Wong
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Article
| Open AccessDNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.
- Lara Kular
- , Yun Liu
- & Maja Jagodic
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Article
| Open AccessIdentifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
To comprehend the genetic regulatory mechanisms underlying brain-related traits in humans, Qi et al. estimate the correlation of expression and DNA methylation QTL effects in cis between blood and brain and show that using blood eQTL/mQTL data of large sample size can increase power in gene discovery for brain-related traits and diseases.
- Ting Qi
- , Yang Wu
- & Jian Yang
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Article
| Open AccessTet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter
Tet-mediated DNA oxidation converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which is essential to regulate different biological processes. Here the authors show that Tet1 and Tet2 regulate mesenchymal stem cell and bone homeostasis through demethylation of P2rX7 promoter.
- Ruili Yang
- , Tingting Yu
- & Songtao Shi
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Article
| Open AccessThe histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity
Steatosis is characterized by initial accumulation of lipids, followed by inflammation and ultimately fibrosis. Here the authors show that the histone demethylase Plant Homeodomain Finger 2 protects liver form steatosis progression by acting as a co-activator of ChREBP, thus, favouring lipid accumulation without inflammation.
- Julien Bricambert
- , Marie-Clotilde Alves-Guerra
- & Renaud Dentin
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Article
| Open AccessIdentification of rare de novo epigenetic variations in congenital disorders
A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.
- Mafalda Barbosa
- , Ricky S. Joshi
- & Andrew J. Sharp
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Article
| Open AccessPostnatal DNA demethylation and its role in tissue maturation
Here the authors show that a large fraction of the tissue-specific methylation pattern is generated postnatally. These changes, which occur in response to hormone signaling, appear to play a major role in the regulation of gene expression and tissue maturation in the liver.
- Yitzhak Reizel
- , Ofra Sabag
- & Howard Cedar
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Article
| Open AccessMethionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width
Methionine availability is known to affect the global levels of histone methylation. Here the authors investigate the metabolically driven dynamics of H3K4me3 and find that methionine availability influences peak width, which is linked to changes in expression of genes associated with cell fate and cancer.
- Ziwei Dai
- , Samantha J. Mentch
- & Jason W. Locasale
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Article
| Open AccessDOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models
Adoptive T cell therapy using an allogeneic T cell graft is an encouraging therapeutic approach in cancer, but issues such as graft-versus-host disease can hinder applicability. Here, the authors show that DOT1L inhibition or DUSP6 overexpression in T cells attenuates graft-versus-host disease but retains anti-tumour activity in mouse models.
- Yuki Kagoya
- , Munehide Nakatsugawa
- & Naoto Hirano
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Article
| Open AccessPCGF5 is required for neural differentiation of embryonic stem cells
Polycomb-group proteins are key regulators of transcriptional programs that maintain cell identity. Here the authors provide evidence that PCGF5, a subunit of Polycomb Repressor Complex 1, is important for the differentiation of mouse embryonic stem cells towards a neural cell fate.
- Mingze Yao
- , Xueke Zhou
- & Hongjie Yao
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Article
| Open AccessParental haplotype-specific single-cell transcriptomics reveal incomplete epigenetic reprogramming in human female germ cells
In mammalian female germ cells, parent-specific epigenetic marks are erased and the X chromosome reactivated before entry into meiosis. Here, by combining parental haplotype reconstruction with single-cell transcriptomics of human female embryonic germ cells, the authors demonstrate that epigenetic reprogramming occurs in a heterogeneous fashion and during a broad time window up to week 14.
- Ábel Vértesy
- , Wibowo Arindrarto
- & Susana M. Chuva de Sousa Lopes
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Article
| Open AccessNOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence
Notch can drive senescence in a cell contact dependent manner. Here the authors show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously via the JAG1-NOTCH-HMGA1 interplay during senescence.
- Aled J. Parry
- , Matthew Hoare
- & Masashi Narita
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Article
| Open AccessA somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing
Previous studies suggest that DNA methylation is the main mechanism to silence endogenous retroviruses (ERVs) in somatic cells. Here the authors provide evidence that distinctive sets of ERVs are silenced by Setdb1 in different types of somatic cells, suggesting a general function in ERV silencing.
- Masaki Kato
- , Keiko Takemoto
- & Yoichi Shinkai
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Article
| Open AccessRNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors
Repression of gene transcription using CRISPR-Cas9 has been achieved in vitro but not for delivery into adult animal models. Here, the authors use AAV8 to deliver the transcriptional repressor dSaCas9KRAB to the cholesterol regulator Pcsk9, and show repression up to 24 weeks and reduced cholesterol levels in mice.
- Pratiksha I. Thakore
- , Jennifer B. Kwon
- & Charles A. Gersbach
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Article
| Open AccessMethylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase
Lysine methylation is increasingly being implicated in the modification of non-histone proteins. Here the authors find that the methylation of DNMT1 and E2F1 are recognized by the protein L3MBTL3 and the ubiquitin E3 ligase CRL4DCAF5, which cooperatively target these methylated proteins for ubiquitin-dependent proteolysis.
- Feng Leng
- , Jiekai Yu
- & Hui Zhang
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Article
| Open AccessOrientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome
The inactive X chromosome condenses into a bipartite structure. Here the authors use cells with allelic deletions or inversions to show that the Dxz4 locus is necessary to maintain the bipartite structure and that Dxz4 orientation controls the distribution of contacts on the inactive X chromosome.
- G. Bonora
- , X. Deng
- & C. M. Disteche
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Article
| Open AccessEpigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation
Although IL-23 is expressed by psoriatic keratinocytes as well as immune cells, only the immune cell derived IL-23 is thought to be important for the development of psoriasis. Here the authors provide evidence that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation.
- Hui Li
- , Qi Yao
- & Cord Brakebusch
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Article
| Open AccessRecurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
Cytosine methyltransferases (DNMTs) often silence transposons in eukaryotic genomes. Here the authors describe the recurrent acquisition of DNMTs by transposons from two distantly-related eukaryotes and suggest that methylation of CG dinucleotides by transposon DNMTs could modify the host epigenome in dinoflagellates.
- Alex de Mendoza
- , Amandine Bonnet
- & Ryan Lister
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Article
| Open AccessGon4l regulates notochord boundary formation and cell polarity underlying axis extension by repressing adhesion genes
Anteroposterior axis extension during gastrulation is dynamically coordinated, but how this is regulated at a molecular level is unclear. Here, the authors show in zebrafish that the chromatin factor Gon4l, encoded by ugly duckling, coordinates axis extension by modulating EpCAM and Integrinα3b expression.
- Margot L. K. Williams
- , Atsushi Sawada
- & Lilianna Solnica-Krezel
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Article
| Open AccessZeb1-Hdac2-eNOS circuitry identifies early cardiovascular precursors in naive mouse embryonic stem cells
The production of nitric oxide (NO) is required for early stage embryo implantation into the uterus. Here the authors show that during differentiation of naive mouse ESCs, early production of endogenous NO leads to a mesendoderm differentiation commitment pathway by inhibiting the action of the transcriptional repressor Zeb1.
- Chiara Cencioni
- , Francesco Spallotta
- & Carlo Gaetano
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Article
| Open AccessHeritable DNA methylation marks associated with susceptibility to breast cancer
DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.
- Jihoon E. Joo
- , James G. Dowty
- & Yoland Antill
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Article
| Open AccessCo-occurring expression and methylation QTLs allow detection of common causal variants and shared biological mechanisms
Most expression QTLs (eQTLs) co-occur with a DNA methylation QTL (meQTL), suggesting a common causal variant. Here the authors analyse DNA and RNA from blood and identify eQTL-meQTL pairs likely to share a causal variant, finding that expression and methylation are often genetically co-regulated.
- Brandon L. Pierce
- , Lin Tong
- & Habibul Ahsan
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Article
| Open AccessExploiting genetic variation to uncover rules of transcription factor binding and chromatin accessibility
Single nucleotide variants (SNVs) can affect chromatin occupancy by transcription factors (TF). Here the authors mine naturally occurring SNVs to probe cis elements and define contextual sequences that govern in vivo transcription factor chromatin occupancy and chromatin accessibility.
- Vivek Behera
- , Perry Evans
- & Gerd A. Blobel
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Article
| Open AccessscNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells
Relationships between DNA methylation and transcription, and methylation and DNA accessibility can be probed but interrogating all three in the same single cells has not been possible. Here, the authors report the first single-cell method for parallel chromatin accessibility, DNA methylation and transcriptome profiling.
- Stephen J. Clark
- , Ricard Argelaguet
- & Wolf Reik
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Article
| Open AccessCytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging
While epigenetic factors have been implicated in the circadian rhythm, the detection of circadian cytosine modifications has remained elusive. Here the authors identify a large number of epigenetically variable cytosines that show circadian oscillations in their modification status in mice.
- Gabriel Oh
- , Sasha Ebrahimi
- & Art Petronis
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Article
| Open AccessNeuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms
Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.
- Christopher H. Douse
- , Stuart Bloor
- & Yorgo Modis
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Article
| Open AccessEpigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood
FGF21 exerts beneficial metabolic effects on multiple tissues. Here the authors show that the Fgf21 gene is demethylated during the postnatal suckling period, creating an epigenetic memory that determines the responsiveness of the Fgf21 gene to inducers such as PPARα activators or fasting in adulthood.
- Xunmei Yuan
- , Kazutaka Tsujimoto
- & Yoshihiro Ogawa
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Article
| Open AccessThe plant-specific histone residue Phe41 is important for genome-wide H3.1 distribution
The canonical histone variant H3.1 of vascular plants contains a conserved Phe residue at position 41 that is unique to the plant kingdom. Here, Lu et al. provide evidence that H3.1Phe41 acts collaboratively with the H3.1 core domain to restrict H3.1 deposition to silent regions of the genome.
- Li Lu
- , Xiangsong Chen
- & Xuehua Zhong
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Article
| Open AccessCARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity
CARM1 is an arginine methyltransferase often overexpressed in human cancer. Here, the authors show that EZH2 inhibition suppresses growth in CARM1-expressing epithelial ovarian cancer, and examine the mechanism of how CARM1 promotes EZH2-mediated tumor suppressor gene silencing.
- Sergey Karakashev
- , Hengrui Zhu
- & Rugang Zhang
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Article
| Open AccessAbsence of warmth permits epigenetic memory of winter in Arabidopsis
Plants use multiple cues to monitor seasonal temperatures. Here, the authors show that Arabidopsis requires not only prolonged cold, but the absence of temperature spikes above 15 °C to epigenetically silence FLC during winter.
- Jo Hepworth
- , Rea L. Antoniou-Kourounioti
- & Caroline Dean
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Article
| Open AccessMethylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin
Cutaneous squamous cell carcinoma (cSCC) is a skin cancer that normally progresses from UV-induced actinic keratosis (AK). Here, the authors investigate the epigenomics of cSCC and highlight two distinct subclasses of AK and cSCC originating from distinct keratinocyte differentiation stages.
- Manuel Rodríguez-Paredes
- , Felix Bormann
- & Frank Lyko
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Article
| Open AccessBMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1
The polycomb group protein BMI1 is highly expressed in prostate cancer. Here, the authors demonstrate that BMI1 directly interacts with AR leading to increased AR signaling independently of PRC1 complex and that targeting BMI1 inhibits tumor growth of castration-resistant prostate cancer tumors.
- Sen Zhu
- , Dongyu Zhao
- & Qi Cao
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Article
| Open AccessA naturally occurring epiallele associates with leaf senescence and local climate adaptation in Arabidopsis accessions
Epigenetic variation underlies various aspects of phenotypic diversity of plants. Here, He et al show a naturally occurring epiallele controls Arabidopsis leaf senescence by regulating the expression of PHEOPHYTIN PHEOPHORBIDE HYDROLASE (PPH), and is associated with local climate adaptation.
- Li He
- , Wenwu Wu
- & Jian-Kang Zhu
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Article
| Open AccessDistinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo
How the cardiac myocyte epigenome is rearranged during development, postnatal maturation and disease is not well understood. Here, the authors investigate the human cardiac myocyte epigenome during development and chronic heart failure and identify distinct epigenetic programs regulating these processes.
- Ralf Gilsbach
- , Martin Schwaderer
- & Lutz Hein
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Article
| Open AccessLsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells
Satellite cells can differentiate both into myocytes and brown adipocytes. Here, the authors show that the histone demethylase Lsd1 prevents adipogenic differentiation of satellite cells by repressing expression of Glis1, and that its ablation changes satellite cell fate towards brown adipocytes and delays muscle regeneration in mice.
- Milica Tosic
- , Anita Allen
- & Roland Schüle