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| Open AccessA biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae
Non-typeable Haemophilus influenzae, which causes ear and lung infections, has a DNA methyltransferase encoded by alternative alleles that are subject to random ON/OFF switching. Here, Atack et al.show that this epigenetic switch controls the expression of key proteins involved in virulence.
- John M. Atack
- , Yogitha N. Srikhanta
- & Michael P. Jennings
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Article
| Open AccessEvolution of dosage compensation under sexual selection differs between X and Z chromosomes
Complete sex chromosome dosage compensation is largely limited to male heterogametic species, with the majority of female heterogametic species displaying incomplete dosage compensation. Here, the authors show that sexual conflict over gene expression combined with sexual selection in males can explain this pattern.
- Charles Mullon
- , Alison E. Wright
- & Judith E. Mank
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Article
| Open AccessFgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells
The transcription factor estrogen-related receptor beta, Esrrb, regulates pluripotency genes in embryonic stem cells, but how it acts in trophoblast stem (TS) cells is unclear. Here, the authors identify Esrrb as a primary target of Fgf/Mek signaling and outline a unique TS cell-specific interactome to sustain stemness.
- Paulina A. Latos
- , Angela Goncalves
- & Myriam Hemberger
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| Open AccessHighly condensed chromatins are formed adjacent to subtelomeric and decondensed silent chromatin in fission yeast
The level of chromatin condensation and gene expression is believed to be inversely correlated. Here the authors show that the transcriptionally silent telomere regions are flanked by highly condensed chromatin, and are less condensed than euchromatin in the interphase of Schizosaccharomyces pombe.
- Atsushi Matsuda
- , Yuji Chikashige
- & Yasushi Hiraoka
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Article
| Open AccessDOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression
DOT1L is an anti-cancer therapeutic target in leukaemia but has a poorly understood role in solid tumours. Here the authors show that DOT1L expression is associated with poor survival and aggressive cancers by helping to epigenetically activate the epithelial-mesenchymal transition during breast cancer progression.
- Min-Hyung Cho
- , Ji-Hye Park
- & Gu Kong
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Article
| Open AccessDNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer
The molecular factors influencing patient response to endocrine therapy are poorly understood. Here Stone et al.characterize the DNA methylome of endocrine response and show that methylation of oestrogen receptor-associated enhancers underpins endocrine sensitivity in human breast cancer.
- Andrew Stone
- , Elena Zotenko
- & Susan J. Clark
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Article
| Open AccessEpigenetic silencing of Oct4 by a complex containing SUV39H1 and Oct4 pseudogene lncRNA
Pseudogene derived long non-coding RNAs (lncRNAs) can regulate the expression of their ancestral genes. Here, the authors show that the Oct4 pseudogene OctP4lncRNA plays an important role in inducing and maintaining silencing of the ancestral Oct4 gene in differentiating mouse embryonic stem cells.
- Michele Scarola
- , Elisa Comisso
- & Roberta Benetti
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BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase
Polycomb repressive complex 1 (PRC1) ubiquitinates histone H2A at lysine 119. Here the authors show that the intrinsically low activity of PCGF4–RING1B, a canonical PRC1 E3 ligase, is offset by a favourable interaction with nucleosome substrates, resulting in efficient site-specific monoubiquitination.
- Asad M. Taherbhoy
- , Oscar W. Huang
- & Andrea G. Cochran
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Article
| Open AccessObesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance
The hormone adiponectin is produced by fat cells and has positive metabolic effects. Here, Kim et al.show that DNA methyltransferase 1 (DNMT1) represses adiponectin expression through hypermethylation of its promoter, and that inflammatory cytokines enhance DNMT1 activity in obese mice and humans.
- A. Young Kim
- , Yoon Jeong Park
- & Jae Bum Kim
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Article
| Open AccessIntegrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma
Rhabdomyosarcoma is a common childhood soft-tissue cancer. Here Seki and Nishimura analyse the exome, transcriptome, copy number and DNA methylome of 60 sarcomas and identify distinct methylation subgroups associated with genetic and clinical features.
- Masafumi Seki
- , Riki Nishimura
- & Junko Takita
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Article
| Open AccessSingle molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes
Bacterial DNA methylation is involved in many processes, from host defense to antibiotic resistance, however current methods for examining methylated genomes lack single-cell resolution. Here Beaulaurier et al. present Single Molecule Modification Analysis of Long Reads, a new tool for de novodetection of epigenetic heterogeneity.
- John Beaulaurier
- , Xue-Song Zhang
- & Gang Fang
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Article
| Open AccessCharacterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants
Currently, genome-wide methylation studies are limited to using targeted arrays or enrichment to assess large sample sizes. Here, Allum et al. demonstrate MethylC-Capture Sequencing, a cost-effective method for investigating genetic and epigenetic variation.
- Fiona Allum
- , Xiaojian Shao
- & Elin Grundberg
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Dissecting the role of aberrant DNA methylation in human leukaemia
Chronic myeloid leukaemia is characterized by the genetic translocation t(9;22) encoding for BCR-ABL oncogene; however, the molecular mechanisms of disease progression are poorly understood. Here Amabile et al. show that aberrant methylation is promoted by BCR-ABL, driving the evolution of the disease.
- Giovanni Amabile
- , Annalisa Di Ruscio
- & Daniel G. Tenen
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| Open AccessReinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency
LIF/STAT3 signalling characterizes naive pluripotency in mouse embryonic stem cells (ESCs), but whether this pathway can sustain a similar state in human cells is not completely understood. Here the authors show that LIF stimulation and enhancement of STAT3 activity allow human ESCs to escape from FGF2 dependency and facilitates their entry into a naive-like state of pluripotency.
- Hongwei Chen
- , Irène Aksoy
- & Pierre Savatier
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| Open AccessMolecular mechanism for USP7-mediated DNMT1 stabilization by acetylation
DNMT1 is a methyl-transferase involved in maintaining tissue-specific patterns of DNA methylation. Here the authors solve the structure of a DNMT1-USP7 complex and demonstrate the mechanism by which DNMT1 stability is regulated through acetylation by preventing association with the deubiquitinase USP7.
- Jingdong Cheng
- , Huirong Yang
- & Yanhui Xu
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Histone deacetylation promotes mouse neural induction by restricting Nodal-dependent mesendoderm fate
Differentiation of embryonic stem cells (ESCs) into neural lineages involves epigenetic changes. Here the authors show that transient histone deacetylation promotes the transition from epiblast stem cells to neural progenitors during mouse ESC differentiation and show that this effect is partly mediated by the restriction of Nodal signalling by histone deacetylase 1.
- Pingyu Liu
- , Xiaoyang Dou
- & Naihe Jing
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Epigenetic variation in the Egfr gene generates quantitative variation in a complex trait in ants
Variation in complex traits is generated by the interaction of genetic and environmental factors. Here, the authors show that genome-wide DNA methylation indirectly regulates quantitative methylation of the Egfrgene to generate continuous size variation of larvae workers in the carpenter ant.
- Sebastian Alvarado
- , Rajendhran Rajakumar
- & Moshe Szyf
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| Open AccessPW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence
Mesoangioblasts are mesodermal stem cells with a therapeutic potential for treatment of muscular dystrophy due to their ability to differentiate into skeletal muscle. This study shows that the PW1/Peg3 protein is crucial for mesoangioblast myogenic and migratory potency and is a therapeutically relevant biomarker.
- Chiara Bonfanti
- , Giuliana Rossi
- & Graziella Messina
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| Open AccessLong-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci
There is a functional link between SNPs and epigenetic variations when they are in close range, but the long-range effect is unclear. Here, by analysing methylation quantitative trait loci, the authors demonstrate that methylation levels at CpG sites in lymphocytes are correlated with distal SNPs.
- Mathieu Lemire
- , Syed H.E. Zaidi
- & Thomas J. Hudson
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Gene silencing by CRISPR interference in mycobacteria
Recombination-based tools for generating targeted mutations in Mycobacterium tuberculosislack efficiency. Here the authors present a CRISPR interference approach that is able to efficiently repress the expression of target genes in mycobacteria, in a rapid and cost-effective manner.
- Eira Choudhary
- , Preeti Thakur
- & Nisheeth Agarwal
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Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children
Food allergy is a growing clinical and public health burden. Here, the authors carry out a genome-wide association study in samples with well-defined allergies to a variety of foods, and identify the 6p21.32 region that significantly increases risk of developing peanut allergy.
- Xiumei Hong
- , Ke Hao
- & Xiaobin Wang
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Developmental enhancers revealed by extensive DNA methylome maps of zebrafish early embryos
DNA methylation undergoes dynamic changes during development and cell differentiation. Here, by comparing DNA methylomes from different stages of embryonic development of the zebrafish, the authors suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis.
- Hyung Joo Lee
- , Rebecca F. Lowdon
- & Ting Wang
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Article
| Open AccessIntermediate DNA methylation is a conserved signature of genome regulation
Many loci in the mammalian genome are intermediately methylated. Here, by comprehensively identifying these loci and quantifying their relationship with gene activity, the authors show that intermediate methylation is an evolutionarily conserved epigenomic signature of gene regulation.
- GiNell Elliott
- , Chibo Hong
- & Joseph F. Costello
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| Open AccessDppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting
Reprogramming of mouse somatic cells into iPSCs often generates pre-iPSCs, low-grade iPSCs that show abnormal Dlk1-Dio3 imprinting, and fully reprogrammed, high-grade iPSCs. Here, the authors show that germ-cell marker Dppa3 enhances reprogramming kinetics, critical for the maintenance of Dlk1-Dio3 imprinting and generation of fully reprogrammed iPSCs.
- Xingbo Xu
- , Lukasz Smorag
- & D. V. Krishna Pantakani
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The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors
The epigenetic modifier EZH2 is highly expressed in melanoma but its role in cancer initiation and progression is still unclear. Here the authors use mouse models and human cell lines to show that EZH2 has an essential role in melanoma progression and metastasis, thus highlighting its potential as a therapeutic target.
- Daniel Zingg
- , Julien Debbache
- & Lukas Sommer
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| Open AccessEpigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance
Histone modification is critical for gene expression regulation during development. Here, the authors show that the demethylase LSD1 and its target gene ATN1are responsible for maintenance of neural progenitor cells during mouse cortical development.
- Feng Zhang
- , Dan Xu
- & Zhiheng Xu
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Article
| Open AccessPaternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications
Following fertilization, the oocyte and sperm lose their distinct chromatin signature to form a functional embryonic genome. Here the authors find that, in human embryos, the paternal constitutive heterochromatin is inherited in the canonical configuration from the sperm and is propagated by the H3K9/HP1 pathway.
- Christine van de Werken
- , Godfried W. van der Heijden
- & Esther B. Baart
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Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development
Regulation of CD4 and CD8 expression during thymic development is a classical model to study control of lineage determination. Here the authors show that Brd1 epigenetically marks CD8 enhancer for activation by mediating H3K14 acetylation, which is necessary for establishing the CD8 T-cell lineage.
- Yuta Mishima
- , Changshan Wang
- & Atsushi Iwama
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A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing
Immune cell pro-inflammatory gene expression is suppressed following prolonged stimulation. Using a chemoproteomic approach, the authors show that methyltransferase G9a forms a protein complex that promotes the transcriptional repressor activity of c-Myc to repress inflammation-induced gene expression.
- Cui Liu
- , Yanbao Yu
- & Xian Chen
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| Open AccessMORC1 represses transposable elements in the mouse male germline
The Microrchidia (Morc) family of GHKL ATPases are important repressors of transposons and other DNA-methylated and silent genes in A. thaliana. Here, the authors show that MORC1 is responsible for repression and methylation of specific classes of transposons in the mouse male germline.
- William A. Pastor
- , Hume Stroud
- & Steven E. Jacobsen
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| Open AccessAn integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
Type 2 diabetes (T2D) is a highly heterogeneous disease with a strong genetic component. Here the authors examine genome-wide methylation patterns in T2D-discordant, T2D-concordant and healthy concordant monozygotic twin pairs, and identify DNA methylation signals that may represent new biomarkers or drug targets for T2D.
- Wei Yuan
- , Yudong Xia
- & Tim D. Spector
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Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis
Systemic sclerosis (SSc) is an incurable disease of unknown cause, characterized by vasculopathy, autoimmunity and fibrosis. Here the authors show that simultaneous decrease in two transcription factors, KLF5 and Fli1, underlies SSc development in mice and represents a signature trait of SSc patients.
- Shinji Noda
- , Yoshihide Asano
- & Shinichi Sato
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| Open AccessAn epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator
Somatic cell reprogramming can induce distinct pluripotent states. Here the authors perform time-resolved whole-genome bisulfite sequencing during the reprogramming of mouse embryonic fibroblasts and report dynamic global DNA methylation changes.
- Dong-Sung Lee
- , Jong-Yeon Shin
- & Jeong-Sun Seo
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| Open AccessDNA methylation signatures link prenatal famine exposure to growth and metabolism
The long-term effect of prenatal nutrition on gene regulation is largely unknown. Here the authors identify differentially methylated regions in whole blood from individuals exposed to famine early after conception, and show that these epigenetic changes may have adverse metabolic consequences later in life.
- Elmar W. Tobi
- , Jelle J. Goeman
- & Bastiaan T. Heijmans
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BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10
BRMS1, a component of the Sin3A–HDAC repressor complex, blocks invasion and migration of breast cancer cells. Here the authors show that BRMS1-like (BRMS1L) inhibits breast cancer metastasis by blocking epithelial to mesenchymal transition through transcriptional suppression of the FZD10 receptor for Wnt ligands.
- Chang Gong
- , Shaohua Qu
- & Erwei Song
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Age-related variations in the methylome associated with gene expression in human monocytes and T cells
The functional relevance of age-related variation in DNA methylation is unclear. Here, Reynolds et al. analyze how patterns of genome-wide gene expression and DNA methylation data vary with age in circulating monocytes and T cells, and report age-associated methylation signals that are correlated with cis-gene expression and vascular aging.
- Lindsay M. Reynolds
- , Jackson R. Taylor
- & Yongmei Liu
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Article
| Open AccessThe role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice
During mouse preimplantation phases, a repressive imprint is imposed on the maternal allele of Xist, which encodes a large non-coding RNA required for X-chromosome inactivation. Here the authors show that trimethylation of histone H3 at lysine 9 on Xist promoter chromatin is responsible for the maternally determined Xistrepression.
- Atsushi Fukuda
- , Junko Tomikawa
- & Akihiro Umezawa
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Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation
Epigenetic changes during the differentiation of bone-resorbing cells have important implications in bone remodelling. Here the authors target this pathway with I-BET151, an inhibitor of bromo and extra-terminal proteins that inhibits expression of the MYC-NFAT axis and suppresses bone loss in multiple mouse models.
- Kyung-Hyun Park-Min
- , Elisha Lim
- & Lionel B Ivashkiv
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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER
Reduced expression of DICER—responsible for the processing of microRNA precursors—was previously linked to poor clinical outcomes in cancer patients. Here, the authors uncover an epigenetic mechanism by which hypoxia suppresses DICER expression and deregulates the miR-200-Zeb1 circuit in breast cancer to promote the tumour phenotype.
- Twan van den Beucken
- , Elizabeth Koch
- & Bradly G. Wouters
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Article
| Open AccessDynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease
DNA methylation is essential for proper gene expression, development and genome stability. Here the authors present whole-genome DNA methylation analyses of purified mouse cardiomyocytes from newborn, adult and failing hearts and find highly dynamic patterns between the three phenotypes of cardiomyocytes.
- Ralf Gilsbach
- , Sebastian Preissl
- & Lutz Hein
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The meta-epigenomic structure of purified human stem cell populations is defined at cis-regulatory sequences
There is epigenetic variability in the same cell type among healthy individuals, but the mechanism or significance of this variability is not clear. Here, the authors purify CD34+ cells from different individuals and use meta-epigenomic approaches to analyse and explain the epigenetic variability observed.
- N. Ari Wijetunga
- , Fabien Delahaye
- & John M. Greally
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Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth
Extreme fetal growth is associated with increased risk of various adult diseases, although the mechanism underlying these associations is poorly understood. Here the authors show that abnormal fetal growth correlates with increased DNA methylation levels and report sex-specific epigenetic patterns associated with fetal growth.
- Fabien Delahaye
- , N. Ari Wijetunga
- & Francine H. Einstein
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Article
| Open AccessA random six-phase switch regulates pneumococcal virulence via global epigenetic changes
Pneumococci can alternate between harmless and highly virulent forms. Here the authors show that such variation may be due to random rearrangements in a genetic locus encoding a restriction-modification system, resulting in epigenetic changes that affect expression of many genes.
- Ana Sousa Manso
- , Melissa H. Chai
- & Marco R. Oggioni
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A prominent and conserved role for YY1 in Xist transcriptional activation
X-chromosome inactivation is a tightly regulated mechanism, which silences one of the two female X chromosomes. Here Makhlouf et al. show that the autosomal transcription factor YY1 directly promotes expression of the XistRNA—a master regulator of X-chromosome inactivation—at the onset of the inactivation process.
- Mélanie Makhlouf
- , Jean-François Ouimette
- & Claire Rougeulle
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| Open AccessEpigenetic silencing of miR-210 increases the proliferation of gastric epithelium during chronic Helicobacter pylori infection
Chronic infection with the bacterium Helicobacter pylori is associated with inflammation and increased risk of gastric cancer. Kiga et al. show that methylation and silencing of the microRNA gene miR-210is associated with infection in humans, and promotes proliferation of gastric epithelial cells in culture.
- Kotaro Kiga
- , Hitomi Mimuro
- & Chihiro Sasakawa
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UNR facilitates the interaction of MLE with the lncRNA roX2 during Drosophila dosage compensation
The process that balances expression of X-chromosomal genes between males and females is under tight regulatory control. Here, Militti et al. show that in Drosophila, the RNA-binding protein UNR functions during dosage compensation to promote the interaction between the RNA helicase MLE and the long non-coding RNA roX2.
- Cristina Militti
- , Sylvain Maenner
- & Fátima Gebauer
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| Open AccessNucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming
Changes in chromatin structure impact gene expression programs by modulating accessibility to the transcription machinery. Here, West et al. explore differences in nucleosome occupancy between mammalian pluripotent and somatic cells and uncover regulatory regions likely to play key roles in determining cell identity.
- Jason A. West
- , April Cook
- & Robert E. Kingston
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Nuclear factor Y-mediated H3K27me3 demethylation of the SOC1 locus orchestrates flowering responses of Arabidopsis
The onset of flowering is a major developmental transition in plants. Here, Hou et al. show that a NF-Y transcription factor complex exerts epigenetic control over the timing of flowering in Arabidopsisby modulating trimethylated H3K27 levels at a floral pathway integrator, SOC1, in response to environmental and intrinsic signals.
- Xingliang Hou
- , Jiannan Zhou
- & Hao Yu
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| Open AccessMatrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression
Soft 3D gels can promote the growth of tumour-repopulating cells, a self-renewing subpopulation of cancer cells critical in cancer progression. Here, the authors investigate the mechanism behind this phenomenon and show that the histone 3 lysine residue 9 methylation and Sox2 are controlling this process.
- Youhua Tan
- , Arash Tajik
- & Ning Wang