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| Open AccessStructure of the human Bre1 complex bound to the nucleosome
The structure of the nucleosome-bound human Bre1 complex reveals that its two RING domains bind the acidic patch and nucleosomal DNA, directing the E2 enzyme and ubiquitin for H2BK120-specific ubiquitination. The binding mode suggests a possible regulatory mechanism through nucleosomal DNA flexibility.
- Shuhei Onishi
- , Kotone Uchiyama
- & Toru Sengoku
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Article
| Open AccessBET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Article
| Open AccessTwo DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Trypanosoma brucei DOT1A and DOT1B methylate H3K76 without H2B-ubiquitin. Based on structural and enzymatic data, Frisbie et al. reveal a mechanism of how these enzymes cooperatively and efficiently tri-methylate H3K76 in a ubiquitin-independent way.
- Victoria S. Frisbie
- , Hideharu Hashimoto
- & Erik W. Debler
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| Open AccessThe chromatin landscape of healthy and injured cell types in the human kidney
Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.
- Debora L. Gisch
- , Michelle Brennan
- & Michael T. Eadon
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Article
| Open AccessHistone lactylation couples cellular metabolism with developmental gene regulatory networks
While metabolic reprogramming has been shown to drive changes in cell identity, the link between cellular metabolism and gene expression remains poorly characterized. Here they show that histone lactylation couples metabolism and transcription during neural crest cell differentiation in the early embryo.
- Fjodor Merkuri
- , Megan Rothstein
- & Marcos Simoes-Costa
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Article
| Open AccessStructure of the complete Saccharomyces cerevisiae Rpd3S-nucleosome complex
In this study, the authors present the cryogenic electron microscopy reconstruction of the Rpd3S complex engaged with a nucleosome. The corresponding model describes the interactions that facilitate histone deacetylation within gene bodies by the Rpd3S complex.
- Jonathan W. Markert
- , Seychelle M. Vos
- & Lucas Farnung
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Article
| Open AccessRelease of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation
Methyl-phos switches on histones have been shown to regulate reader protein displacement from chromatin. However, in this study the authors find that H3T3ph is not required to remove transcription factors from H3K4me3 in mitosis. This might help to preserve promoter properties during cell division.
- Rebecca J. Harris
- , Maninder Heer
- & Jonathan M. G. Higgins
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Article
| Open AccessAn autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering
Here, using small molecule antagonists and protein engineering, the authors identify an autoinhibited state of 53BP1 leading to its chromatin binding surface being obstructed. Such small molecule ligands present a potential avenue for the development of cancer therapy drugs.
- Gaofeng Cui
- , Maria Victoria Botuyan
- & Georges Mer
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Article
| Open AccessNEUROD1 reinforces endocrine cell fate acquisition in pancreatic development
Errors during pancreas development and specification of the endocrine lineage can result in severe neonatal diabetes. Here they show that loss of NEUROD1 leads to disturbances in endocrine cell identity acquisition during pancreas development, with cellular reprogramming occurring at the single-cell level within both α- and β-cell populations.
- Romana Bohuslavova
- , Valeria Fabriciova
- & Gabriela Pavlinkova
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Article
| Open AccessThe COMPASS subunit Spp1 protects nascent DNA at the Tus/Ter replication fork barrier by limiting DNA availability to nucleases
The Spp1 subunit of Set1C is recruited to the Tus/Ter replication fork barrier via its PHD domain and protects the replication fork by preventing excessive ssDNA formation, stressing the importance of chromatin structure in the replication stress response.
- Nagham Ghaddar
- , Yves Corda
- & Vincent Géli
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Article
| Open AccessTAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition
The E1A binding protein p300 and its close paralogue CREB-binding protein are transcriptional coactivators with intrinsic histone acetyltransferase activity. Here, the authors show that the TAZ2 domain of p300 has a HAT autoinhibitory function that is relieved upon binding of transcription factors.
- Longxia Xu
- , Hongwen Xuan
- & Xiaobing Shi
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Article
| Open AccessHistone H3 serine-57 is a CHK1 substrate whose phosphorylation affects DNA repair
Histone post-translational modifications control several fundamental processes on DNA. Here, the authors describe a conserved phosphorylation of histone H3 on the globular core and show that it loosens the nucleosome and regulates DNA repair.
- Nikolaos Parisis
- , Pablo D. Dans
- & Daniel Fisher
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Article
| Open AccessHdac1 and Hdac2 regulate the quiescent state and survival of hair-follicle mesenchymal niche
Cell division and stem cell maintenance are tightly linked. Here they show that in the hair follicle an epigenetic mechanism maintains mesenchymal niche dormancy in a highly proliferative microenvironment while repurposing mitogenic signaling to orchestrate the hair cycle clock.
- Hadas Sibony-Benyamini
- , Emil Aamar
- & David Enshell-Seijffers
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| Open AccessGetting personal with epigenetics: towards individual-specific epigenomic imputation with machine learning
The authors present eDICE, an attention-based model that enables accurate imputation of missing portions of the observed epigenetic landscape, and show that eDICE can be used to predict individualspecific epigenomic variation in the EN-TEx dataset.
- Alex Hawkins-Hooker
- , Giovanni Visonà
- & Gabriele Schweikert
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Article
| Open AccessMolecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome
The mechanism by which the chromatinized HBV genome is transcribed remains poorly understood. In this study, Liu et al. demonstrate how HBx exploits Spindlin1, a histone methylation reader, to overcome heterochromatin barriers and enhance HBV transcription from the cccDNA minichromosome.
- Wei Liu
- , Qiyan Yao
- & Haitao Li
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Article
| Open AccessEzh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.
- Julie Rondeaux
- , Déborah Groussard
- & Sylvain Fraineau
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| Open AccessMOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters
Here the authors show that epigenetic regulation through the histone acetyltransferase MOF and the acetylation of histone H4 lysine 16 affect essential functions in the mitochondria and primary cilia. This regulation is important to promote epidermal differentiation and hair follicle formation.
- Dongmei Wang
- , Haimin Li
- & Rui Yi
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Article
| Open AccessThe cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells
Niemann-Pick type C disease is characterized by deficiency of the endolysosomal cholesterol transporter NPC1. Here, the authors show in Npc1−/− mice that loss of NPC1 impairs oligodendrocyte lineage cell differentiation and developmental myelination through perturbed epigenetic regulation.
- Thaddeus J. Kunkel
- , Alice Townsend
- & Andrew P. Lieberman
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Article
| Open AccessASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair
Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.
- Corina Maritz
- , Reihaneh Khaleghi
- & Hanspeter Naegeli
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| Open AccessHistone exchange sensors reveal variant specific dynamics in mouse embryonic stem cells
Eviction of histones from nucleosomes and their exchange with newly synthesized or alternative variants is a central epigenetic determinant. Here the authors implement a molecular sensor that reports on steady-state exchange of histones in mESC and mice revealing dependency between deposition of histone variant H3.3 and exchange of H3.1 and H2B in both open and closed chromatin.
- Marko Dunjić
- , Felix Jonas
- & Yonatan Stelzer
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Article
| Open AccessChemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid
Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.
- Severin Lechner
- , Raphael R. Steimbach
- & Bernhard Kuster
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Article
| Open AccessImpaired histone inheritance promotes tumor progression
Here the authors show disturbing parental histone inheritance in cancer cells drives tumor progression by reprogramming the epigenetic profile and conferring fitness advantages to some of the newly emerged subclones.
- Congcong Tian
- , Jiaqi Zhou
- & Haiyun Gan
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Article
| Open AccessA crucial role for dynamic expression of components encoding the negative arm of the circadian clock
A screen for clock mutants uncovered a conserved novel auxiliary NuA4 histone acetylase complex, containing orthologs of BRD-8 and BYE-1, needed for maintaining the timely Negative Element expression required for sustaining a normal circadian rhythm.
- Bin Wang
- , Xiaoying Zhou
- & Jay C. Dunlap
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Article
| Open AccessACL and HAT1 form a nuclear module to acetylate histone H4K5 and promote cell proliferation
Xu et al. showed that a histone acetyltransferase interacts with an acetyl-CoA synthetic enzyme for histone acetylation to stimulate gene expression and endosperm cell division, pointing to a mechanism coupling energy metabolism to epigenetics.
- Qiutao Xu
- , Yaping Yue
- & Dao-Xiu Zhou
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Article
| Open AccessCryo-EM structure of the Saccharomyces cerevisiae Rpd3L histone deacetylase complex
The Rpd3L HDAC complex is an ancient chromatin-modifying complex found in diverse eukaryotes. Here, authors describe the cryo-EM structure of the yeast complex and show that key features are preserved in the human complex.
- Avinash B. Patel
- , Jinkang Qing
- & Yuan He
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Article
| Open AccessMechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex
SIN3B is a histone deacetylase part of the holo-SIN3 complex. Here by cryo-electron microscopy we unveil the assembly, activation, specificity, and substrate recognition of the human SIN3B histone deacetylase complex.
- Mandy S. M. Wan
- , Reyhan Muhammad
- & Claudio Alfieri
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Article
| Open AccessThe AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner
rAAV vectors vary in their effectiveness between species, making it difficult to predict clinical outcomes. Here authors show that AAV capsid proteins influence the vector epigenomic state in cells, and that a single amino acid change in the vector can alter the vector epigenome and hence transgene expression levels between species.
- Adriana Gonzalez-Sandoval
- , Katja Pekrun
- & Mark A. Kay
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Article
| Open AccessHistone 4 lysine 5/12 acetylation enables developmental plasticity of Pristionchus mouth form
Developmental plasticity allows organisms to match traits to their environment, however, there are few known molecular mechanisms underlying such plasticity. Here, the authors show that feeding morphs in adult Pristionchus nematodes are set during a critical window in juveniles and identify H4K5/12ac as the environmental information carrier.
- Michael S. Werner
- , Tobias Loschko
- & Ralf J. Sommer
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Article
| Open AccessMOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
Altered transcriptional machinery promotes aberrant self-renewal of non-stem hematopoietic progenitors. Here the authors show that AF10 fusion proteins cause aberrant self-renewal via ENL, which promotes leukemic transformation by binding to MOZ/MORF lysine acetyltransferases
- Yosuke Komata
- , Akinori Kanai
- & Akihiko Yokoyama
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Article
| Open AccessPhosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence
Little is known about the role of glycolysis in cellular senescence. Here, authors report that glycolysis-derived serine biosynthesis activates PKM2 to phosphorylate histone H3T11, prevent cell senescence, and promote healthy aging.
- Yinsheng Wu
- , Lixu Tang
- & Xilan Yu
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Article
| Open AccessA CpG island-encoded mechanism protects genes from premature transcription termination
Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
- Amy L. Hughes
- , Aleksander T. Szczurek
- & Robert J. Klose
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Article
| Open AccessRSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells
Pluripotency is coordinated at multiple levels of gene expression. Here the authors show that ribosome biogenesis is tightly regulated in embryonic stem cells (ESC) to control the translation of transcription and chromatin factors and dictate ESC fate.
- Sébastien Durand
- , Marion Bruelle
- & Mathieu Gabut
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Article
| Open AccessSimultaneous profiling of histone modifications and DNA methylation via nanopore sequencing
The interplay between histone modifications and DNA methylation plays a crucial role in establishing and maintaining the epigenomic landscape. Here, the authors develop a nanopore sequencing based method for mapping histone modifications and DNA methylation from native, long, single DNA molecules.
- Xue Yue
- , Zhiyuan Xie
- & Yimeng Yin
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Article
| Open AccessStructural insights into p300 regulation and acetylation-dependent genome organisation
Here the authors use structural analyses to show that an intrinsically disordered transcription activation domain in the oncogene BRD4-NUT binds to and activates p300. This in-turn drives formation of higher-order, acetylation-dependent chromatin condensates.
- Ziad Ibrahim
- , Tao Wang
- & Daniel Panne
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Article
| Open AccessDOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal
How and whether histone modifications regulate distinct gene networks remains insufficiently understood. Here Cattaneo et al show that DOT1L catalyzed H3K79me2 regulates fetal chamber-specific gene expression and neonatal cardiomyocyte cell cycle withdrawal to coordinate heart development.
- Paola Cattaneo
- , Michael G. B. Hayes
- & Sylvia M. Evans
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Article
| Open AccessEnhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity
The role of enhancer de-regulation in anti-tumor immunity remains to be explored. Here, the authors suggest that ablation of MLL3 and MLL4, two enhancer-associated H3K4 monomethyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response.
- Hanhan Ning
- , Shan Huang
- & Deqing Hu
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Article
| Open AccessMYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.
- Hiroki Takahashi
- , Ge Yang
- & Juro Sakai
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Article
| Open AccessDominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm
Silencing of endogenous retroviruses is crucial for maintaining transcriptional and genomic integrity of cells and is maintained by histone H3K9 methylation and/or DNA methylation in various cell types. Here the authors show that loss of DNA methyltransferase DNMT1 in endoderm results in ERV derepression while H3K9me3 is unaltered.
- Zeyang Wang
- , Rui Fan
- & Gunnar Schotta
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Article
| Open AccessTranscription-coupled and epigenome-encoded mechanisms direct H3K4 methylation
Methylation of histone H3 lysine 4 is associated with transcription. Here the authors describe three Arabidopsis methyltransferases that direct H3K4me1 and propose that one methyltransferase works co-transcriptionally while the others are recruited to genomic and epigenomic features.
- Satoyo Oya
- , Mayumi Takahashi
- & Soichi Inagaki
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Article
| Open AccessPRC1-mediated epigenetic programming is required to generate the ovarian reserve
In humans, the ovarian reserve is maintained over decades by meiotic arrest of oocytes. Here the authors show that Polycomb Repressive Complex 1 (PRC1)-mediated epigenetic programming is essential for formation of ovarian reserve and thus female reproductive lifespan.
- Mengwen Hu
- , Yu-Han Yeh
- & Satoshi H. Namekawa
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Article
| Open AccessPCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression
Variant Polycomb complexes can have tissue-specific roles during development. Here they show that PCGF6 controls lineage-specification in human PSCs by promoting neuroectoderm differentiation and repressing mesendoderm differentiation via distinct downstream targets.
- Xianchun Lan
- , Song Ding
- & Wei Jiang
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Article
| Open AccessHistone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes
DNMT3A is known to methylate DNA at histone H3 lysine 36 (H3K36me3)-marked transcriptionally active regions in mouse oocytes. Here the authors show that DNMT3A is also guided by H3K36me2 to methylate broad domains in genic and intergenic loci, as well as on the X chromosome. These two histone marks together comprise the minimal chromatin signature for global DNA methylation in mouse oocytes.
- Seiichi Yano
- , Takashi Ishiuchi
- & Hiroyuki Sasaki
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Article
| Open AccessTRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
Gonadal fate in mammals is determined during embryogenesis and is actively maintained in adulthood. This study shows that E3-SUMO ligase activity of TRIM28 is required for ovarian identity maintenance and testicular-specific gene repression in mouse adult ovary; in its absence, ovarian granulosa cells transdifferentiate to Sertoli cells.
- Moïra Rossitto
- , Stephanie Déjardin
- & Francis Poulat
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Article
| Open AccessHSF1 phosphorylation establishes an active chromatin state via the TRRAP–TIP60 complex and promotes tumorigenesis
Here the authors show phosphorylation of heat shock factor 1 (HSF1) at S419 via the chromatin-bound kinase PLK1, promotes HSF1 recruitment of histone acetyltransferases and histone acetylation reader proteins TRIM33 and TRIM24, which actually also execute histone H2BK120 mono-ubiquitination at target genes. Furthermore, HSF1 phosphorylation has an impact on melanoma cell proliferation.
- Mitsuaki Fujimoto
- , Ryosuke Takii
- & Akira Nakai
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Article
| Open AccessCD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
Understanding CD8 + T cell response to immune checkpoint blockade at the molecular level is important for the design of more efficient cancer immune therapies. Authors show here that the histone lysine methyltransferase Suv39h1 controls the transcriptional programs that determine the functionality of CD8 + T cells and Suv39h1 inhibition may potentiate anti-PD-1 therapy of melanomas.
- Leticia Laura Niborski
- , Paul Gueguen
- & Eliane Piaggio
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Article
| Open AccessSMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters
SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.
- Yanjun Zhang
- , Yuan Fang
- & Dong Fang
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Article
| Open AccessIntegrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction
Here they perform an integrative analysis of the epigenetic landscape of human pluripotent stem cell hematopoietic differentiation and show that JUNB is an indispensable transcription factor for hemogenic endothelium development.
- Xia Chen
- , Peiliang Wang
- & Jie Na
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Article
| Open AccessChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.
- Lorna A. Farrelly
- , Shuangping Zheng
- & Ian Maze
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Article
| Open AccessDNA sequence-dependent formation of heterochromatin nanodomains
The ability to predict epigenetic regulation is an important challenge in biology. Here the authors describe heterochromatin nanodomains (HNDs) and compare four different types of H3K9me2/3-marked HNDs in mouse embryonic stem cells. They further develop a computational framework to predict genome-wide HND maps from DNA sequence and protein concentrations, at single-nucleotide resolution.
- Graeme J. Thorn
- , Christopher T. Clarkson
- & Vladimir B. Teif