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| Open AccessThe H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs
How the histone variant H2A.Z controls cell fate remains unclear. Here, the authors reveal that the H2A.Z interacting partner HMG20A plays a key role in regulating transcription during early head and heart development.
- Andreas Herchenröther
- , Stefanie Gossen
- & Sandra B. Hake
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Article
| Open AccessHistone H3.3 deposition in seed is essential for the post-embryonic developmental competence in Arabidopsis
Producing vigorous seeds that can germinate and establish seedlings is vital for plant propagation. Here, the authors report the critical function of histone variant H3.3 in establishing chromatin accessibility and seed vigour in Arabidopsis.
- Ting Zhao
- , Jingyun Lu
- & Danhua Jiang
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Article
| Open AccessThe chromatin remodeller ATRX facilitates diverse nuclear processes, in a stochastic manner, in both heterochromatin and euchromatin
The chromatin remodeling complex ATRX can promote gene expression, for example by binding G-quadruplexes (G4s) to prevent their negative effect on expression. Here the authors use a single-cell approach to show that only a subset of erythroid cells isolated from patients with ATRX mutations have reduced chromatin accessibility and alpha globin expression, suggesting a stochastic process.
- Julia Truch
- , Damien J. Downes
- & Richard J. Gibbons
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| Open AccessHistone variant H2A.Z regulates zygotic genome activation
During embryogenesis, the genome becomes transcriptionally active in a process known as zygotic genome activation (ZGA); how ZGA is initiated is still an open question. Here the authors show histone variant H2A.Z deposition precedes RNA polymerase II binding on chromatin, before ZGA. H2A.Z loss causes transcriptional downregulation of ZGA genes and leads to changes in the 3D genome organization.
- Dafne Ibarra-Morales
- , Michael Rauer
- & Nicola Iovino
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| Open AccessMorc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation
Endogenous retroviruses (ERVs) compose a significant portion of mammalian genomes; however, how ERVs are regulated is not well known. Here the authors performed a genome-wide sgRNA screen to identify Morc3 as a mediator of ERV silencing. They show Morc3 associates with the H3.3 chaperone Daxx, and that loss of Morc3 leads to reduced H3.3 at ERVs.
- Sophia Groh
- , Anna Viktoria Milton
- & Gunnar Schotta
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Article
| Open AccessATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress
ATRX is a chromatin remodeling protein, which loss has been associated to replication stress, DNA damage, and DNA repair failures that drive genome instability. Here the authors reveal that ATRX protects genomic integrity at G4-containing regions by maintaining these regions in a closed heterochromatic state.
- Yu-Ching Teng
- , Aishwarya Sundaresan
- & Laura A. Banaszynski
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| Open AccessHIRA stabilizes skeletal muscle lineage identity
The epigenetic mechanisms coordinating the maintenance of adult cellular lineages remain poorly understood. Here the authors demonstrate that HIRA, a H3.3 histone chaperone, establishes the chromatin landscape required for skeletal muscle cell identity.
- Joana Esteves de Lima
- , Reem Bou Akar
- & Frédéric Relaix
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Article
| Open AccessThe histone variant H2A.W and linker histone H1 co-regulate heterochromatin accessibility and DNA methylation
T-DNA mutants have been widely used for Arabidopsis gene function characterization. Here, by characterizing a null mutant created by CRISPR, the authors show that previous reported function of H2A.W is confounded by a T-DNA insertion induced chromosomal rearrangement and reveal its role in regulating heterochromatin accessibility.
- Pierre Bourguet
- , Colette L. Picard
- & Olivier Mathieu
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Article
| Open AccessMutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas
Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers that have been associated with mutations in ATRX. Here the authors reveal a functional role of histone demethylases KDM4B in regulating ALT activation.
- M. Udugama
- , L. Hii
- & L. H. Wong
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Article
| Open AccessMultiple roles of H2A.Z in regulating promoter chromatin architecture in human cells
Histone variant H2A.Z has been suggested to contribute to the regulation of promoter accessibility. Here, the authors present high-depth maps of the position and accessibility of H2A.Z-containing nucleosomes for human Pol II promoters and provide evidence that H2A.Z has multiple and distinct roles in regulating gene expression dependent upon its location in a promoter.
- Lauren Cole
- , Sebastian Kurscheid
- & David J. Tremethick
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Article
| Open AccessNon-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation
Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.
- Pierre-Eric Lutz
- , Marc-Aurèle Chay
- & Gustavo Turecki
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| Open AccessPositioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation
The order of DNA methylation and histone modifications during transcription remained unclear. Here the authors show that HMGA2 induces DNA nicks at TGFB1-responsive genes, promoting nucleosome incorporation containing γ-H2AX, which is required for repair-mediated DNA demethylation and transcription.
- Stephanie Dobersch
- , Karla Rubio
- & Guillermo Barreto
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Article
| Open AccessAn embryonic stem cell-specific heterochromatin state promotes core histone exchange in the absence of DNA accessibility
Nucleosome turnover concomitant with incorporation of the histone variant H3.3 is a hallmark of regulatory regions in the animal genome. Here, the authors demonstrate that fast histone turnover and H3.3 incorporation defines a dynamic heterochromatin state in pluripotent stem cells.
- Carmen Navarro
- , Jing Lyu
- & Simon J. Elsässer
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| Open AccessGenome-wide chromatin accessibility is restricted by ANP32E
Chromatin state underlies cellular function, and transcription factor binding patterns along with epigenetic marks define chromatin state. Here the authors show that the histone chaperone ANP32E functions through regulation of H2A.Z to restrict genome-wide chromatin accessibility and to inhibit gene transcriptional activation.
- Kristin E. Murphy
- , Fanju W. Meng
- & Patrick J. Murphy
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| Open AccessNAP1-RELATED PROTEIN1 and 2 negatively regulate H2A.Z abundance in chromatin in Arabidopsis
The histone variant H2A.Z is deposited by the SWR1 complex to replace H2A in Arabidopsis, but the mechanism of H2A.Z removal is unclear. Here, the authors show that NRP proteins can regulate gene expression by counteracting SWR1 and prevent excessive accumulation of H2A.Z.
- Yafei Wang
- , Zhenhui Zhong
- & Israel Ausin
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Article
| Open AccessHistone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination
Histone ubiquitination plays a critical role in the DNA damage response pathway. Here the authors reveal how RNF168 ubiquitinates the H2A family including noncanonical variants, H2AZ and macroH2A1/2, at the divergent N-terminal tail lysine residue.
- Jessica L. Kelliher
- , Kirk L. West
- & Justin W. C. Leung
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| Open AccessDistinct roles for H4 and H2A.Z acetylation in RNA transcription in African trypanosomes
Histone modification and deposition are key regulators of transcription. Here, Kraus et al. provide a quantitative histone acetylome for Trypanosoma brucei, identify histone modifications enriched at transcription start sites, and show how H4 and H2A.Z acetylation affect histone deposition and transcription in trypanosomes.
- Amelie J. Kraus
- , Jens T. Vanselow
- & T. Nicolai Siegel
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| Open AccessPARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
The poly(ADP-ribose) polymerases play a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. Here the authors characterize the kinetics of PARP1 binding to a variety of nucleosomes harbouring DNA double-strand breaks.
- Deepti Sharma
- , Louis De Falco
- & Curt A. Davey
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| Open AccessMapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq)
The authors introduce ACT-seq: a Tn5-based method for rapidly profiling epigenetic marks in bulk-cell and single-cell samples. ACT-seq avoids many laborious or time-consuming steps required for similar techniques including chromatin fragmentation and end repair.
- Benjamin Carter
- , Wai Lim Ku
- & Keji Zhao
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| Open AccessH3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans
Substitution of lysine 27 with methionine in histone H3.3 (H3.3K27M) is a driver mutation of pediatric high-grade gliomas. Here the authors show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans, through JNK pathway misregulation.
- Kamila Delaney
- , Maude Strobino
- & Florian A. Steiner
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| Open AccessInterspecies conservation of organisation and function between nonhomologous regional centromeres
Although the centromere-specific histone CENP-A usually assembles on specific genomic sequences, centromeric DNA is not conserved. Here the authors characterize the genome and centromeres of related fission yeasts and provide evidence that Schizosaccharomyces centromere DNA possesses intrinsic conserved properties that promote assembly of CENP-A chromatin.
- Pin Tong
- , Alison L. Pidoux
- & Robin C. Allshire
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| Open AccessAtomic resolution cryo-EM structure of a native-like CENP-A nucleosome aided by an antibody fragment
CENP-A histone variants replace histones H3 at centromeres. Here the authors use a single-chain antibody fragment (scFv) to stabilize human CENP-A nucleosome containing a native α-satellite DNA and solved its structure by cryo-EM to 2.6 Å resolution, providing insight into the structure and function of the CENP-A nucleosome.
- Bing-Rui Zhou
- , K. N. Sathish Yadav
- & Ping Zhang
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Article
| Open AccessZnhit1 controls intestinal stem cell maintenance by regulating H2A.Z incorporation
Lgr5+ stem cells in intestinal crypts are critical for gut epithelium homeostasis. Here, the authors show that Znht1 critically regulates intestinal homeostasis by promoting interaction between histone variant H2A.Z and its chaperone YL1 to incorporate H2A.Z into genes involved in intestinal stem cell fate.
- Bing Zhao
- , Ying Chen
- & Xinhua Lin
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| Open AccessThe CENP-A centromere targeting domain facilitates H4K20 monomethylation in the nucleosome by structural polymorphism
Kinetochore function depends on H4K20 monomethylation in centromeric nucleosomes but the underlying mechanism is unclear. Here, the authors provide evidence that the centromere-specific nucleosome subunit CENP-A facilitates H4K20 methylation by enabling a conformational change of the H4 N-terminal tail.
- Yasuhiro Arimura
- , Hiroaki Tachiwana
- & Hitoshi Kurumizaka
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| Open AccessMacroH2A1 chromatin specification requires its docking domain and acetylation of H2B lysine 20
The histone variant macroH2A1 localizes to two functionally distinct chromatin subtypes marked by either H3K27me3 or H2B acetylations. Here the authors identify the features of macroH2A1 required for its recruitment to H2B-acetylated chromatin and identify H2BK20 acetylation as a critical requirement for this recruitment.
- Penelope D. Ruiz
- & Matthew J. Gamble
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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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Article
| Open AccessInhibition of a K9/K36 demethylase by an H3.3 point mutation found in paediatric glioblastoma
Recent studies have identified a number of oncogenic histone point mutations in different cancers. Here the authors provide evidence that H3.3 G34R substitution mutation, which is found in paediatric gliomas, causes changes in H3K9me3 and H3K36me3 by interfering with the KDM4 family of K9/K36 demethylases.
- Hsiao P. J. Voon
- , Maheshi Udugama
- & Lee H. Wong
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Article
| Open AccessFunctional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit
The HIRA histone chaperone complex is involved in the deposition of the histone variant H3.3. Here the authors, by using biochemical and crystallographic approaches, report the homotrimerization of the HIRA subunit which is critical for the functional activity of the complex.
- Dominique Ray-Gallet
- , M. Daniel Ricketts
- & Geneviève Almouzni
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| Open AccessLive-cell single-molecule dynamics of PcG proteins imposed by the DIPG H3.3K27M mutation
Diffuse intrinsic pontine gliomas exhibit a characteristic mutation of lysine 27 to methionine (K27M) in genes encoding histone H3.3. Here the authors show that the H3.3K27M mutation imposes a specific pattern of H3.3K27 methylation by altering the target search dynamics of PcG proteins.
- Roubina Tatavosian
- , Huy Nguyen Duc
- & Xiaojun Ren
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| Open AccessGlobal H3.3 dynamic deposition defines its bimodal role in cell fate transition
Histone variant H3.3 is incorporated at transcriptionally active genes and is associated with active marks. Here, the authors investigate H3.3 deposition during reprogramming and find that initially H3.3 helps maintain parental cell fate and is later required for establishment of the cell lineages.
- Hai-Tong Fang
- , Chadi A. EL Farran
- & Yuin-Han Loh
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| Open AccessHistone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
H2AX is a histone variant with an essential function in DNA double-strand break repair and genome stability. Here, Weyemi and colleagues show that loss of neuronal H2AX leads to locomotor dysfunction and alteration in oxidative stress response.
- Urbain Weyemi
- , Bindu D. Paul
- & Solomon H. Snyder
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| Open AccessFunctional crosstalk between histone H2B ubiquitylation and H2A modifications and variants
Ubiquitylation of H2B is associated with transcription and regulation of chromatin structure. Here, the authors perform an unbiased screen to identify the role of chromatin modifications on ubiquitylation of H2BK120 and characterize the crosstalk between H2BK120ub and H2A modifications and variants.
- Felix Wojcik
- , Geoffrey P. Dann
- & Tom W. Muir
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| Open AccessStructural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX
The ATRX-DAXX histone chaperone complex incorporates H3.3 in heterochromatin in a replication-independent manner. Here, the authors present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX, and characterize ATRX-dependent and-independent functions of DAXX.
- Dominik Hoelper
- , Hongda Huang
- & Peter W. Lewis
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| Open AccessH2A.Z controls the stability and mobility of nucleosomes to regulate expression of the LH genes
Chromatin architecture at promoters can influence gene transcription. Here, the authors use a biophysical approach to elucidate how DNA sequence and histone variant usage modulate the properties of nucleosomes at the promoters of two target genes.
- Sergei Rudnizky
- , Adaiah Bavly
- & Ariel Kaplan
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Article
| Open AccessWriting of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner
Epigenome editing by zinc finger (ZF) and CRISPR-dCas9 technologies can induce or repress gene expression. Here, the authors show that histone methyltransferase PRDM9 fused to either dCas9 or ZF proteins can sustain gene re-expression, and H3K79me is required for stable gene re-expression.
- David Cano-Rodriguez
- , Rutger A F. Gjaltema
- & Marianne G Rots
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Article
| Open AccessThe histone variant H2A.X is a regulator of the epithelial–mesenchymal transition
The histone H2A variants are involved in DNA repair, gene regulation and cancer development. In this study, the authors unravel an additional role for H2A.X in the regulation of mesenchymal-like traits and activation of the EMT transcription factors, Slug and ZEB1, in colon cancer cells.
- Urbain Weyemi
- , Christophe E. Redon
- & William M. Bonner
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Structural analyses of the chromatin remodelling enzymes INO80-C and SWR-C
INO80-C and SWR-C are chromatin remodelling enzymes with roles in transcription pathways. Here, the authors show that they both have similar architectures displaying a ‘tail’ domain and a heterohexameric ‘head’ domain, with conformational changes influencing nucleosomal binding and enzyme activity.
- Shinya Watanabe
- , Dongyan Tan
- & Craig L. Peterson
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Histone H3.3 and its proteolytically processed form drive a cellular senescence programme
Cellular senescence involves extensive structural changes to chromatin, but the role of histone variants and histone cleavage is unknown. Here, Duarte et al.identify histone variant H3.3 and its proteolytically processed form lacking a portion of the N-terminal tail as key regulators of senescence.
- Luis F. Duarte
- , Andrew R. J. Young
- & Emily Bernstein
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MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency
Chromatin templates can act as barriers against cellular reprogramming. Gaspar-Maia and colleagues use mouse models deficient in the histone variants macroH2A1 and macroH2A2, and find that macroH2A functions as an epigenetic barrier against induced pluripotency by silencing Utx target genes.
- Alexandre Gaspar-Maia
- , Zulekha A. Qadeer
- & Emily Bernstein