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| Open AccessDissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity
Polycomb repressive complexes PRC1 and PRC2 act non-redundantly at target genes to regulate transcription. Here the authors present engineered mouse ESCs targeting the PRC2 subunits EZH1 and EZH2 to discriminate between contributions of distinct H3K27 methylation states and the presence of PRC2/1 at chromatin, and provide evidence for the role of H3K27 acetylation in PRC2-mediated functions.
- Elisa Lavarone
- , Caterina M. Barbieri
- & Diego Pasini
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Article
| Open AccessRdDM-independent de novo and heterochromatin DNA methylation by plant CMT and DNMT3 orthologs
Whether plants have true DNMT3 orthologs and their role in establishing DNA methylation are still unclear. Here, the authors show that DNMT3s are persistent through plant evolution and mediates both de novo and heterochromatin DNA methylation in the early divergent land plant Physcomitrella patens.
- Rafael Yaari
- , Aviva Katz
- & Nir Ohad
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Article
| Open AccessMultiplexed Cas9 targeting reveals genomic location effects and gRNA-based staggered breaks influencing mutation efficiency
Designing effective genome engineering strategies requires an understanding of the impact that genomic locus has on CRISPR-Cas9 activity. Here the authors use TRIP integrations to profile editing outcomes genome-wide and observe that gRNA sequence influences the structure of the double strand break.
- Santiago Gisler
- , Joana P. Gonçalves
- & Maarten van Lohuizen
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Article
| Open AccessThe maternal to zygotic transition regulates genome-wide heterochromatin establishment in the zebrafish embryo
Eukaryotic genomes are segregated into euchromatin and heterochromatin. Here the authors show that heterochromatin establishment during zebrafish embryo development is controlled by zygotic transcription of miR-430 and subsequent degradation of maternal transcripts encoding the chromatin remodeling protein Smarca2.
- Kathrin Laue
- , Srivarsha Rajshekar
- & Mary G. Goll
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Article
| Open AccessTargeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells
The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition
- Evelyne Lima-Fernandes
- , Alex Murison
- & Catherine A. O’Brien
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Article
| Open AccessAtypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor
H2B monoubiquitination is implicated in oncogenesis. Here, the authors show that UBR7 PHD finger is a H2BK120 monoubiquitin ligase that acts a tumour suppressor in breast cancer by suppressing gene expression for EMT, while promoting expression of CDH4 which restrain WNT/β-cat pathway.
- Santanu Adhikary
- , Deepavali Chakravarti
- & Chandrima Das
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| Open AccessParent of origin genetic effects on methylation in humans are common and influence complex trait variation
Parent-of-origin effects (POE) are observed when there are different effects from alleles inherited from the two parents on phenotypic measures. Here, Zeng et al. study POE on DNA methylation in 5,101 individuals and identify genetic variants that associate with methylation variation via POE and their potential phenotypic consequences.
- Yanni Zeng
- , Carmen Amador
- & Chris S. Haley
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Article
| Open AccessSMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells
Tight regulation of retrotransposons such as endogenous retroviruses (ERVs) is essential for genome and transcriptome integrity. Here, the authors show that the ATPase function of the chromatin remodeler SMARCAD1 facilitates the binding of KAP1 to ERVs and is required for their repression in embryonic stem cells.
- Parysatis Sachs
- , Dong Ding
- & Jacqueline E. Mermoud
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Article
| Open AccessThe Arabidopsis H3K27me3 demethylase JUMONJI 13 is a temperature and photoperiod dependent flowering repressor
Jumonji domain-containing histone demethylases regulate flowering in plants. Here Zheng et al. show that Arabidopsis JMJ13 is an H3K27me3 demethylase that recognizes H3K27me3 via hydrogen bonding and hydrophobic interactions and affects both photoperiod and temperature-dependent flowering responses.
- Shuzhi Zheng
- , Hongmiao Hu
- & Jiamu Du
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Article
| Open AccessSperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans
The mechanisms of paternal epigenetic inheritance and its influence on offspring are still poorly understood. Here the authors provide evidence that in C. elegans, sperm-inherited chromatin states influence transcription and cell identity in the germ cells of offspring.
- Kiyomi Raye Kaneshiro
- , Andreas Rechtsteiner
- & Susan Strome
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Article
| Open AccessReversible histone glycation is associated with disease-related changes in chromatin architecture
Proteins continuously undergo non-enzymatic modifications such as glycation, which accumulate under physiological conditions but can be enhanced in disease. Here the authors characterise histone glycation, provide evidence that it affects chromatin, particularly in breast cancer, and identify DJ-1 as a deglycase.
- Qingfei Zheng
- , Nathaniel D. Omans
- & Yael David
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Article
| Open AccessH3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
Lysine27-to-methionine mutations in histone H3 genes (H3K27M) occur in a subgroup of gliomas and decrease genome-wide H3K27 trimethylation. Here the authors utilise primary H3K27M tumour lines and isogenic CRISPR-edited controls and show that H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3.
- Ashot S. Harutyunyan
- , Brian Krug
- & Jacek Majewski
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Article
| Open AccessImpact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
Somatic heterozygous TET2 loss drives clonal hematopoiesis, which is linked to malignant cell degeneration and potentially cardiovascular disease. Here, the authors investigate the molecular impact of a germline TET2 mutation in a lymphoma family, finding elevated blood DNA methylation levels and no predisposition to atherosclerosis
- Eevi Kaasinen
- , Outi Kuismin
- & Lauri A. Aaltonen
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Article
| Open AccessDissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements
Obesity and related metabolic complications represent an important health burden. Here the authors carry out a methylC-capture sequencing-based epigenome-wide association study to link circulating plasma lipid levels, CpG methylation and cardiometabolic risk across adipose and blood tissues.
- Fiona Allum
- , Åsa K. Hedman
- & Elin Grundberg
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Article
| Open AccessThe molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells
Transcription factor (TF) networks are essential for the molecular identity of each cell type. Here, the authors show that TF Nanog utilises multiple molecular strategies to enhance embryonic stem cell self-renewal, which include regulation of chromatin accessibility in the presence of LIF or maintenance of H3K27me3 at developmental regulators in its absence.
- Victor Heurtier
- , Nick Owens
- & Pablo Navarro
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Article
| Open AccessDeconvolution of single-cell multi-omics layers reveals regulatory heterogeneity
Heterogeneity in gene expression and epigenetic states exists across individual cells. Here, the authors develop scCAT-seq, a technique for simultaneously performing ATAC-seq and RNA-seq within the same single cell.
- Longqi Liu
- , Chuanyu Liu
- & Xun Xu
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Article
| Open AccessMaintenance of epigenetic landscape requires CIZ1 and is corrupted in differentiated fibroblasts in long-term culture
The inactive X chromosome (Xi) is a model for establishment and maintenance of repressed chromatin and the function of polycomb repressive complexes. Here the authors show that Xi transiently relocates from the nuclear periphery during replication in a CIZ1-dependent manner, which plays a role in maintaining PRC-mediated repressed chromatin.
- Emma R. Stewart
- , Robert M. L. Turner
- & Dawn Coverley
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| Open AccessReplication timing and epigenome remodelling are associated with the nature of chromosomal rearrangements in cancer
The connection between DNA replication timing and changes that occur to the epigenome in cancer are still poorly understood. Here, the authors perform Repli-Seq and integrated epigenome analyses and find that genomic regions that undergo long-range epigenetic deregulation in prostate cancer also show concordant differences in replication timing.
- Qian Du
- , Saul A. Bert
- & Susan J. Clark
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Article
| Open AccessBAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation
In Drosophila, the Calypso–ASX complex catalyzes H2A deubiquitination and aids Polycomb in transcriptional silencing. Here the authors show that the orthologous complex, BAP1.com, promotes gene activation by counteracting PRC1-mediated gene silencing.
- Antoine Campagne
- , Ming-Kang Lee
- & Raphaël Margueron
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Article
| Open AccessAberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming
There are distinct hypermethylation patterns in gene promoters in hepatocellular carcinomas (HCCs). Here, the authors show that the enhancer of C/EBPβ is recurrently hypomethylated in human HCCs, recapitulating this in a transgenic murine model and linking aberrant enhancer hypomethylation to hepatocarcinogenesis.
- Lei Xiong
- , Feng Wu
- & Ka-Fai To
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Article
| Open AccessDNA methylation in mice is influenced by genetics as well as sex and life experience
DNA methylation is an epigenetic mark involved in gene regulation. Here the authors investigate the extent to which genetics, sex and pregnancy influence genomic DNA methylation in mice, providing evidence of the stability of CpG methylation across generation and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology.
- Sara A. Grimm
- , Takashi Shimbo
- & Paul A. Wade
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Article
| Open AccessA conserved dimer interface connects ERH and YTH family proteins to promote gene silencing
In fission yeast, Erh1, ortholog of human ERH, interacts with the YTH family RNA binding protein Mmi1 to form the Erh1-Mmi1 complex (EMC), which has been implicated in gene silencing. Here, the authors present the cocrystal structure of Erh1 homodimers interacting with Mmi1 and further characterise the role of EMC in facultative heterochromatin assembly and gene silencing.
- Guodong Xie
- , Tommy V. Vo
- & Shiv I. S. Grewal
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Article
| Open AccessIntergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila
Animal studies have shown that the nutritional status of parents can predispose the offspring to obesity and obesity-related diseases. Here the authors show that cardiac dysfunction induced by a high-fat diet persists for two generations in Drosophila, and that targeted expression of ATGL/bmm in the offspring, as well as inhibition of H3K27 trimethylation, is cardioprotective.
- Maria Clara Guida
- , Ryan Tyge Birse
- & Rolf Bodmer
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Article
| Open AccessTransposable elements are regulated by context-specific patterns of chromatin marks in mouse embryonic stem cells
Transposable elements (TEs) fulfill essential but poorly understood roles in genome organization and gene expression control. Here the authors show that the regulation of TEs occurs through overlapping epigenetic mechanisms that control the expression and chromatin signatures at TEs.
- Jiangping He
- , Xiuling Fu
- & Andrew P. Hutchins
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Article
| Open AccessThe non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome
The inactive X chromosome (Xi) has an atypical structure, with global loss of TADs, A/B compartments and formation of mega-domains. Here the authors show that the non-canonical SMC family protein, SmcHD1, important for developmental gene silencing on Xi, antagonises TAD formation and compartmentalization on the Xi in a transcription independent way.
- Michal R. Gdula
- , Tatyana B. Nesterova
- & Neil Brockdorff
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Article
| Open AccessEzh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf
Ezh2 is an histone methyltransferase that catalyzes H3K27me3. Here the authors show that Ezh2 promotes T follicular helper (TFH) differentiation and helper activity, by cooperating with Tcf1 to activate Bcl6 transcription and epigenetically repressing p19Arf, an antagonist of Bcl6 function and TFH cell survival.
- Fengyin Li
- , Zhouhao Zeng
- & Hai-Hui Xue
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Article
| Open AccessSCL/TAL1 cooperates with Polycomb RYBP-PRC1 to suppress alternative lineages in blood-fated cells
Mechanisms that operate during embryonic development to restrict cell fate are currently under investigation. Here the authors characterise the role of SCL/TAL1 at the onset of blood specification in embryonic development using mouse EB differentiation culture as a model system.
- Hedia Chagraoui
- , Maiken S. Kristiansen
- & Catherine Porcher
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Article
| Open AccessHistone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis
Histone lysine demethylases (KDMs) can mediate transcriptional reprogramming in disease states. Here the authors show that KDM3A promotes left ventricular hypertrophy and cardiac fibrosis by activating the transcription of Timp1, and that pharmacological inhibition of KDM3A attenuates cardiac remodeling induced by pressure overload.
- Qing-Jun Zhang
- , Tram Anh T. Tran
- & Zhi-Ping Liu
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Article
| Open AccessBinding of HMGN proteins to cell specific enhancers stabilizes cell identity
HMGN1 and HMGN2 are ubiquitous nucleosome binding proteins. Here the authors provide evidence that HMGN proteins preferentially localize to chromatin regulatory sites to modulate the plasticity of the epigenetic landscape, proposing that HGMNs stabilize, rather than determine, cell identity.
- Bing He
- , Tao Deng
- & Michael Bustin
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Article
| Open AccessPan-cancer characterisation of microRNA across cancer hallmarks reveals microRNA-mediated downregulation of tumour suppressors
miRNAs have emerged as regulators of diverse biological processes including cancer. Here the authors present an extended pan-cancer analysis of the miRNAs in 15 epithelial cancers; integrating methylation, transcriptomic and mutation data they reveal alternative mechanisms of tumour suppressors’ regulation in absence of mutation, methylation or copy number alterations.
- Andrew Dhawan
- , Jacob G. Scott
- & Francesca M. Buffa
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Article
| Open AccessHoney bee Royalactin unlocks conserved pluripotency pathway in mammals
Royal jelly is the queen-maker for the honey bee that also has effects on longevity, fertility, and regeneration in mammals. Here the authors provide evidence that its major protein component Royalactin, and the mammalian structural analog Regina, maintain pluripotency in mouse ESCs by activating a ground-state pluripotency-like gene network.
- Derrick C. Wan
- , Stefanie L. Morgan
- & Kevin C. Wang
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Article
| Open AccessEpigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker
DNA methylation is an epigenetic modification that control genetic programs. Here, the authors found that the methylation landscape influences the physicochemical properties of DNA and that it can serve as a universal cancer biomarker, and developed a one-step assay for the detection of cancer DNA.
- Abu Ali Ibn Sina
- , Laura G. Carrascosa
- & Matt Trau
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| Open AccessComprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease
The methylation status of circulating cell-free DNA (cfDNA) can be informative about recent cell death events. Here the authors present an approach to determine the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types, and find that cfDNA from patients reveals tissue contributions that agree with clinical findings.
- Joshua Moss
- , Judith Magenheim
- & Yuval Dor
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Article
| Open AccessThe Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression
Myoblast fusion in skeletal muscle is a complex process but how this is regulated is unclear. Here, the authors identify Ash1L, a histone methyltransferase, as modulating myoblast fusion via activation of the myogenesis gene Cdon, and observe decreased Ash1L expression in Duchenne muscular dystrophy.
- Ilaria Castiglioni
- , Roberta Caccia
- & Davide Gabellini
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| Open AccessCross-species interference of gene expression
- Irene de Bruijn
- & Koen J. F. Verhoeven
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Article
| Open AccessMegadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape
The mammalian inactive X-chromosome (Xi) is organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Here the authors provide evidence that megadomains do not precede Xist expression or Xi gene silencing, and suggest that Dxz4, Firre, and megadomains are dispensable for Xi silencing and escape from X-inactivation.
- John E. Froberg
- , Stefan F. Pinter
- & Jeannie T. Lee
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Article
| Open AccessTopoisomerase 3β interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila
Topoisomerases solve topological problems during DNA metabolism, but their role in RNA metabolism remains unclear. Here the authors provide evidence that in Drosophila, Topoisomerase 3β interacts biochemically and genetically with the RNAi-induced silencing complex (RISC) to promote heterochromatin formation and transcriptional silencing.
- Seung Kyu Lee
- , Yutong Xue
- & Weidong Wang
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Article
| Open AccessDetecting heritable phenotypes without a model using fast permutation testing for heritability and set-tests
Standard approaches for heritability and set testing in statistical genetics rely on parametric models that might not hold in reality and give inflated p-values. Here, the authors develop a fast method for permutation-based testing of marker sets and of heritability that does not suffer from model misspecification.
- Regev Schweiger
- , Eyal Fisher
- & Eran Halperin
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Article
| Open AccessAge-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration
While young muscle faithfully regenerates damaged myofibers, aged muscle is impaired. Here the authors show the “anti-aging” protein α-Klotho is upregulated in young muscle after damage via promoter demethylation and this regulation is lost in aging, resulting in mitochondrial damage and an impaired healing response.
- A. Sahu
- , H. Mamiya
- & F. Ambrosio
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Article
| Open AccessREX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice
REX1 has been shown to regulate pluripotency of ESCs, genomic imprinting and preimplantation development in mice. Here the authors provide evidence that REX1 is the prime target of RNF12 E3 ubiquitin ligase and that Rex1 removal rescues the Rnf12 knockout phenotype in imprinted X chromosome inactivation in mice.
- Cristina Gontan
- , Hegias Mira-Bontenbal
- & Joost Gribnau
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Article
| Open AccessEpigenetic profiling for the molecular classification of metastatic brain tumors
The treatment of brain metastases is often limited by the ability to diagnose their origins. Here the authors generate DNA methylomes from the three most frequent types of brain metastases, identify epigenetic signatures specific to each type of metastasis and construct a DNA methylation-based classifier (BrainMETH) to advance brain metastasis diagnosis.
- Javier I. J. Orozco
- , Theo A. Knijnenburg
- & Diego M. Marzese
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Article
| Open AccessStructural insights into the π-π-π stacking mechanism and DNA-binding activity of the YEATS domain
YEATS domains are histone acylation readers that recognize crotonyllysine and acetyllysine. Here the authors provide structural insights into how YEATS domains recognize acetyllysines and further show that the human AF9 YEATS domain also binds DNA.
- Brianna J. Klein
- , Kendra R. Vann
- & Tatiana G. Kutateladze
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Article
| Open AccessArabidopsis AGDP1 links H3K9me2 to DNA methylation in heterochromatin
DNA methylation and H3K9 dimethylation are two linked epigenetic marks of silenced chromatin in plants that depend on the activity of CMT3/2 and SUVH4/5/6. Here the authors identify AGDP1 as an H3K9me2-binding protein required for heterochromatic non-CG DNA methylation, H3K9 dimethylation, and transcriptional silencing.
- Cuijun Zhang
- , Xuan Du
- & Jian-Kang Zhu
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Article
| Open AccessTracing the transitions from pluripotency to germ cell fate with CRISPR screening
Primordial Germ Cell-Like Cells (PGCLCs) are an in vitro model for primordial germ cell development. Here, the authors couple a novel compound reporter with CRISPR screening to identify key genes for exit from pluripotency and acquisition of PGCLC fate; specifically identifying Nr5a2 and Zfp296.
- Jamie A. Hackett
- , Yun Huang
- & M. Azim Surani
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Article
| Open AccessPWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex
PWWP2A is a chromatin-binding transcriptional regulator that mediates mitosis-progression. Here, the authors provide evidence that PWWP2A directly interacts with H2A.Z nucleosomes, DNA and H3K36me3, binds to an MTA1-specific subcomplex of the NuRD complex (M1HR) and promotes changes to histone acetylation.
- Stephanie Link
- , Ramona M. M. Spitzer
- & Sandra B. Hake
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Article
| Open AccessMiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging
miR-34 is known to regulate age-related gene expression in the Drosophila brain, and miR-34 overexpression can attenuate neurodegeneration induced by polyQ-expanded proteins. Here, Kennerdell and colleagues show that miR-34 confers longevity and neuroprotection via an epigenetic regulator Polycomb Repressive Complex 2 and molecular chaperone expression.
- Jason R. Kennerdell
- , Nan Liu
- & Nancy M. Bonini
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Article
| Open AccessDivergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages
The role of the genome structure in the establishment of the embryonic and trophoblast lineages is still not well understood. Here the authors perform promoter capture Hi-C in mouse trophoblast and embryonic stem cells and find divergent networks of repressive and active chromatin interactions between the two lineages.
- Stefan Schoenfelder
- , Borbala Mifsud
- & Miguel R. Branco
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Article
| Open AccessThe H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells
Epigenetic regulation is critical for the maintenance of germ cell identity. Here the authors show that H3K9me3-mediated gene silencing is critical for repression of testis-specific transcription in Drosophila female germ cells, indicating H3K9me3 maintains female germ cell sexual identity.
- Anne E. Smolko
- , Laura Shapiro-Kulnane
- & Helen K. Salz
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Article
| Open AccessCell cycle-resolved chromatin proteomics reveals the extent of mitotic preservation of the genomic regulatory landscape
Mitosis poses a challenge for transcriptional programs, as it is thought that several proteins lose binding on condensed chromosomes. Here, the authors analyze the chromatin-bound proteome through the cell cycle, revealing retention of most transcription factors and preservation of the regulatory landscape.
- Paul Adrian Ginno
- , Lukas Burger
- & Dirk Schübeler