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The miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis
Differentiation of stem and progenitor cells is a highly regulated process. Here, the authors uncover miR-144 and its target Hmgn2 as the backbone of the genetic regulatory circuit that controls the terminal differentiation of erythrocytes in vertebrates.
- Dmitry A. Kretov
- , Leighton Folkes
- & Daniel Cifuentes
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| Open Access
Functionalized graphene-oxide grids enable high-resolution cryo-EM structures of the SNF2h-nucleosome complex without crosslinking
Nucleosome-protein complexes stick to the air-water interface and denature upon plunge freezing for cryoEM. Here, authors Chio and Palovcak et al. develop EM grids that protect such complexes and use these grids to study the ATP-dependent chromatin remodeler SNF2h.
- Un Seng Chio
- , Eugene Palovcak
- & Yifan Cheng
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| Open Access
Phase-separated CCER1 coordinates the histone-to-protamine transition and male fertility
Here the authors reveal that phase‐separated nuclear CCER1 condensates are required for male fertility by mediating chromatin condensation and histone epigenetic modification, while loss‐of‐function variants of human CCER1 are pathogenic in patients with nonobstructive azoospermia (NOA).
- Dongdong Qin
- , Yayun Gu
- & Zhibin Hu
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| Open Access
The environmentally-regulated interplay between local three-dimensional chromatin organisation and transcription of proVWX in E. coli
Here, the authors use the proVWXoperon of Escherichia coli as a model system to show how the nucleoid associated protein H-NS regulates gene expression in vivo by local chromatin remodelling.
- Fatema-Zahra M. Rashid
- , Frédéric G. E. Crémazy
- & Remus T. Dame
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Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics
The role of histone deacetylases (HDACs) in glioblastoma brain tumour stem cells (BTSCs) remains to be explored. Here, pharmacological inhibition and genetic loss of function approaches show that HDAC2 leads to the maintenance of BTSC growth and self-renewal through its association with the components of the TGF-β signalling pathway.
- Ravinder K. Bahia
- , Xiaoguang Hao
- & Samuel Weiss
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| Open Access
The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming
This study demonstrates that an evolutionary conserved, autoregulatory ‘AT-hook’ domain of SWI/SNF regulates gene transcription and enhancer activation by modulating SWI/SNF intrinsic catalytic activity and is critical for cell lineage priming.
- Dhurjhoti Saha
- , Solomon Hailu
- & Blaine Bartholomew
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A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
Many key developmental transcriptional regulators are broadly expressed but perform distinct functions in specific tissues. Here they show that ubiquitously expressed PBX factors gain limb bud functionality by interaction with HAND2, uncovering fundamental principles of cooperation between promiscuous and tissue-specific regulators to instruct developmental programs.
- Marta Losa
- , Iros Barozzi
- & Licia Selleri
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Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation
MBD proteins are integral subunits of the NuRD complex, a crucial regulator of cellular differentiation. Here the authors systematically dissect which MBD protein domains and isoforms are essential for neuronal differentiation.
- Nina Schmolka
- , Ino D. Karemaker
- & Tuncay Baubec
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| Open Access
Dynamic chromatin architecture of the porcine adipose tissues with weight gain and loss
Here the authors study diet-induced weight gain/loss to identify chromatin architectures in adipose tissue (AT) associated obesity in a pig model. They found parallels and species-specific regulatory elements in humans and pigs that underpin AT specialization.
- Long Jin
- , Danyang Wang
- & Mingzhou Li
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| Open Access
The NuRD complex cooperates with SALL4 to orchestrate reprogramming
Somatic reprogramming involves both transcriptional and epigenetic resetting, but we don’t yet fully understand this process. Here they show that Jdp2, Glis1, Esrrb, and Sall4 can mediate reprogramming by recruiting the NuRD complex to close chromatin, highlighting a potential role in cell fate control.
- Bo Wang
- , Chen Li
- & Duanqing Pei
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Article
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BRD9-mediated chromatin remodeling suppresses osteoclastogenesis through negative feedback mechanism
Osteoclast differentiation is critical for bone homeostasis. The authors show the negative feedback regulation of BRD9-mediated chromatin remodeling on osteoclastogenesis via interferon beta signaling and its therapeutic potential for bone diseases.
- Jiahui Du
- , Yili Liu
- & Xinquan Jiang
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Article
| Open Access
CTCF controls three-dimensional enhancer network underlying the inflammatory response of bone marrow-derived dendritic cells
The role of 3D genome organization is not well understood in the transcriptional regulation of dendritic cells. Here the authors show that activation of dendritic cells in vitro induces dynamic reprogramming of the chromatin looping and enhancer activity linked to changes in gene expression and implicates a role for the chromatin architecture protein CTCF in the inflammatory response of dendritic cells.
- Bobae Yang
- , Sueun Kim
- & Hyoung-Pyo Kim
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Article
| Open Access
Adaptive partitioning of a gene locus to the nuclear envelope in Saccharomyces cerevisiae is driven by polymer-polymer phase separation
Partitioning of active genes to the nuclear periphery is commonly observed but not understood. Here, the authors show that this process occurs by phase separation of transcriptionally active chromatin providing for efficient mRNA transport and memory.
- Lidice González
- , Daniel Kolbin
- & Stephen W. Michnick
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| Open Access
Functional crosstalk between the cohesin loader and chromatin remodelers
Chromatin remodelers direct the cohesin loader to nucleosome depleted regions where cohesin accesses chromosomes. Muñoz et al. now show that the cohesin loader in turn is a biochemical activator of a chromatin remodeler, helping to clear nucleosomes
- Sofía Muñoz
- , Andrew Jones
- & Frank Uhlmann
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Structure of nucleosome-bound human PBAF complex
BAF and PBAF are SWI/SNF family chromatin remodeling complexes that create nucleosome-depleted regions for transcription activation. Here the authors report the structure of a 13-subunit human PBAF in complex with acetylated nucleosome in ADP-BeF3-bound state that provides structural insights into PBAF-mediated nucleosome association.
- Li Wang
- , Jiali Yu
- & Yanhui Xu
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| Open Access
The role of auxiliary domains in modulating CHD4 activity suggests mechanistic commonality between enzyme families
CHD4 is an essential chromatin remodelling enzyme in complex organisms. Here the authors demonstrate that CHD4 activity is regulated both positively and negatively by distinct auxiliary domains, revealing parallels with other chromatin remodellers.
- Yichen Zhong
- , Hakimeh Moghaddas Sani
- & Joel P. Mackay
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DOT1L 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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| Open Access
Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
Renal tubular epithelial cells (TECs) can initiate an adaptive or maladaptive response after injuries of different severity. Here, the authors elucidate a chromatin-mediated mechanism underlying the responses of TECs to varying kidney injuries.
- Xinyi Cao
- , Jiuchen Wang
- & Lirong Zhang
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| Open Access
PICH acts as a force-dependent nucleosome remodeler
In anaphase, any unresolved DNA entanglements between the segregating sister chromatids can give rise to chromatin bridges. Here, the authors present an in vitro single-molecule assay that mimics chromatin under tension, to show that PICH is a tension- and ATP-dependent nucleosome remodeler.
- Dian Spakman
- , Tinka V. M. Clement
- & Gijs J. L. Wuite
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A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Protein degraders are an emerging drug modality; however, their properties lie beyond typical drug-like space. Here the authors report optimisation via structure-based exit vector and linker design towards the VHL-recruiting PROTAC ACBI2, an orally bioavailable and selective degrader of SMARCA2.
- Christiane Kofink
- , Nicole Trainor
- & William Farnaby
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| Open Access
Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation
Here the authors delineate the dynamic changes in 3D genome and epigenome of differentiating macrophages and during infection with Mycobacterium tuberculosis. They reveal a role for NF-κB upon infection and identify SNPs in disease-susceptible loci, including rs1873613 that is located in the anchor of a dynamic chromatin loop.
- Da Lin
- , Weize Xu
- & Gang Cao
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| Open Access
XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair
Cells employ global genome nucleotide excision repair to repair a broad spectrum of genomic DNA lesions. Here, the authors reveal how chromatin is primed for repair, providing insight into mechanisms of chromatin plasticity during DNA repair.
- Charlotte Blessing
- , Katja Apelt
- & Martijn S. Luijsterburg
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Article
| Open Access
Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud
The embryonic limb bud is known to be patterned by a Shh morphogen gradient, though how Shh expression is activated remains less clear. Here the authors show that Etv2 acts as a pioneer transcription factor to mediate accessibility of the ZRS enhancer and initiate Shh expression.
- Naoko Koyano-Nakagawa
- , Wuming Gong
- & Daniel J. Garry
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| Open Access
Satellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells
Here the authors show satellite transcripts in mouse embryonic stem cells drive HP1α into droplets in vitro and also control HP1α organisation and association with chromatin in vivo. Depleting the satellite transcripts converts heterochromatin into a less dynamic and more static state and leads to chromosome instability.
- Clara Lopes Novo
- , Emily V. Wong
- & Peter J. Rugg-Gunn
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| Open Access
The 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 Access
Sex-specific multi-level 3D genome dynamics in the mouse brain
Here the authors provide evidence that 3D chromatin structure in the mouse brain differs between males and females and undergoes dynamic remodelling during the female ovarian cycle. They show female-specific 3D genome dynamics affects neuronal gene expression and brain disorder-relevant genes, and could play a role in reproductive hormone-induced brain plasticity and female-specific risk for brain disorders.
- Devin Rocks
- , Mamta Shukla
- & Marija Kundakovic
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| Open Access
BRD4 promotes resection and homology-directed repair of DNA double-strand breaks
BRD4 is a multifunctional regulator of chromatin binding that plays a direct role in DNA double-strand break repair. BRD4 interacts with the SWI/SNF chromatin remodeling complex and resection machinery to promote homologous recombination.
- John K. Barrows
- , Baicheng Lin
- & David T. Long
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Regulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity
Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
- Reuben Franklin
- , Yiming Guo
- & Sihem Cheloufi
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| Open Access
Menin directs regionalized decidual transformation through epigenetically setting PTX3 to balance FGF and BMP signaling
The decidualization of endometrial stroma is critical for pregnancy maintenance. Here the authors reveal that Menin ensures the expression of PTX3 through H3K4me3 modification, to balance the BMP and FGF signal in the decidua for normal pregnancy.
- Mengying Liu
- , Wenbo Deng
- & Shuangbo Kong
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A compendium of chromatin contact maps reflecting regulation by chromatin remodelers in budding yeast
The effect of ATP-dependent chromatin remodelers on 3D genome organization has not been well studied. Here the authors employ in situ Hi-C with an auxin-inducible degron system to degrade chromatin remodelers in yeast to find that the 3D structure of chromatin collapses in their absence. The chromatin remodeling can modulate 3D architecture depending on chromosomal context and cell cycle stage.
- Hyelim Jo
- , Taemook Kim
- & Daeyoup Lee
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HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape
Genome-wide occupancy of the master circadian clock transcription factor BMAL1::CLOCK varies across tissues and is reprogrammed in cancers, but how specificity is governed is not known. Here the authors show BMAL1::CLOCK in liver tissue is guided by chromatin accessibility remodeled by HNF4A, shedding new lights onto mechanisms of dysregulated circadian rhythms in hepatocarcinoma.
- Meng Qu
- , Han Qu
- & Steve A. Kay
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Article
| Open Access
Conserved and species-specific chromatin remodeling and regulatory dynamics during mouse and chicken limb bud development
The vertebrate limb bud is a paradigm to uncover the fundamental mechanisms that govern embryogenesis and evolutionary diversification. Here the authors compare mouse and chicken limb bud development to study the impact of genome evolution on conserved and divergent gene regulatory interactions.
- Shalu Jhanwar
- , Jonas Malkmus
- & Rolf Zeller
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| Open Access
A CDK-regulated chromatin segregase promoting chromosome replication
How cells coordinate chromatin dynamics with the cell cycle machinery to promote genome duplication during S phase is still a matter of study. Here the authors reveal by in vitro reconstitution assays that the AAA + -ATPase containing Yta7 protein in S. cerevisiae promotes chromatin.
- Erika Chacin
- , Priyanka Bansal
- & Christoph F. Kurat
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OCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human
Although the interactors of pluripotency factors have been identified in mouse embryonic stem cells (ESCs), their interactors in human ESCs remain unexplored. Here the authors map OCT4 protein interactions in naïve and primed human ESCs to find specific interactions with BAF subunits that promote an open chromatin architecture at blastocyst-associated genes and ectodermal genes, respectively.
- Xin Huang
- , Kyoung-mi Park
- & Thorold W. Theunissen
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Reactivation of a developmentally silenced embryonic globin gene
Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.
- Andrew J. King
- , Duantida Songdej
- & Christian Babbs
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| Open Access
Si-C is a method for inferring super-resolution intact genome structure from single-cell Hi-C data
Constructing valid super-resolution intact genome 3D structures from single-cell Hi-C data is essential in investigating chromosome folding. Here the authors develop a method that makes it possible to visualize and investigate chromosome folding in individual cells at the genome scale
- Luming Meng
- , Chenxi Wang
- & Qiong Luo
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| Open Access
Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome
The oncogenic chromatin remodeler ALC1 (amplification in liver cancer 1), also known as CHD1L is an ATP-dependent chromatin remodeler that relaxes chromatin and plays an important role in the poly(ADP-ribose) polymerase 1 -mediated DNA repair pathway. Here, the authors present the ALC1 crystal structure and a cryo-EM structure of ALC1 bound to a nucleosome, which reveal that ALC1 is autoinhibited and how it becomes activated.
- Li Wang
- , Kangjing Chen
- & Zhucheng Chen
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Article
| Open Access
ATRX 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 Access
Genome information processing by the INO80 chromatin remodeler positions nucleosomes
DNA sequence preferences or statistical positioning of histones has not explained genomic patterns of nucleosome organisation in vivo. Here, the authors establish DNA shape/mechanics as key elements that have evolved together with binding sites of DNA sequence-specific barriers so that such information directs nucleosome positioning by chromatin remodelers.
- Elisa Oberbeckmann
- , Nils Krietenstein
- & Sebastian Eustermann
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| Open Access
Ruler elements in chromatin remodelers set nucleosome array spacing and phasing
Although chromatin remodelers have been shown to align nucleosome arrays to barriers and to generate spacing regularity among nucleosomes within arrays, it has remained unclear how the distance to barrier and the spacing length are determined in absolute terms. Here, the authors reveal that remodelers contain a ‘ruler’ element that sets remodeler-specific alignment and spacing distances when generating nucleosome arrays.
- Elisa Oberbeckmann
- , Vanessa Niebauer
- & Philipp Korber
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Article
| Open Access
Impact of DNA methylation on 3D genome structure
Multi-layered epigenetic regulation in higher eukaryotes makes it challenging to disentangle the individual effects of modifications on chromatin structure and function. Here, the authors expressed mammalian DNA methyltransferases in yeast, which have no DNA methylation, to show that methylation has intrinsic effects on chromatin structure.
- Diana Buitrago
- , Mireia Labrador
- & Modesto Orozco
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Article
| Open Access
The box C/D snoRNP assembly factor Bcd1 interacts with the histone chaperone Rtt106 and controls its transcription dependent activity
Biogenesis of small nucleolar RNAs ribonucleoproteins (snoRNPs) requires dedicated assembly machinery. Here, the authors show that a subset of snoRNP assembly factors interacts, genetically or directly, with factors modulating chromatin architecture, suggesting a link between ribosome formation and chromatin functions.
- Benoît Bragantini
- , Christophe Charron
- & Bruno Charpentier
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Article
| Open Access
Pre-mitotic genome re-organisation bookends the B cell differentiation process
During differentiation, chromosome conformation is remodelled to support lineage-specific transcriptional programs. Here, the authors characterise chromosome conformational changes in B lymphocytes as they differentiate into plasma cells, and provide evidence that chromosome reconfiguration occurs prior to DNA replication and mitosis and guides gene expression that controls differentiation.
- Wing Fuk Chan
- , Hannah D. Coughlan
- & Rhys S. Allan
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Article
| Open Access
Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma
The mechanisms behind acquired resistance to the proteasome inhibitor bortezomib in multiple myeloma remain to be elucidated. Here, the authors show that the histone methyltransferase NSD2 stabilized SRC-3 protein levels, promotes its phase separation and alters H3K36me2 at certain gene promoters resulting in a transcriptional profile that favors resistance of myeloma cells to bortezomib.
- Jing Liu
- , Ying Xie
- & Zhiqiang Liu
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Article
| Open Access
Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice
The dynamics of chromatin and transcriptional changes underlying Huntington’s disease remain poorly understood. Here the authors use a Huntington’s mouse model to profile the striatal chromatin landscape, finding that the Huntington’s mutation accelerates age-dependent epigenetic and transcriptional changes, and locally affects 3D chromatin organization.
- Rafael Alcalá-Vida
- , Jonathan Seguin
- & Karine Merienne
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| Open Access
Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors
Primary effusion lymphoma (PEL) has a very poor prognosis. Here, the authors perform H3K27ac HiChIP in PEL cells and generate the PEL enhancer connectome, linking enhancers and promoters in PEL, as well as super-enhancers to dependency factors.
- Chong Wang
- , Luyao Zhang
- & Bo Zhao
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Article
| Open Access
Dinucleosome specificity and allosteric switch of the ISW1a ATP-dependent chromatin remodeler in transcription regulation
Here the authors show that the preference of yeast chromatin remodeler ISW1a for dinucleosomes hinges on conformational changes that occur in the transition from binding mononucleosomes to dinucleosomes. These changes are critical for ISW1a organizing chromatin at promoters and regulating transcription in conjunction with other chromatin remodelers.
- Saurabh K. Bhardwaj
- , Solomon G. Hailu
- & Blaine Bartholomew
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Article
| Open Access
CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks
Chromatin is dynamically remodeled in response to DNA damage in favour of repair. Here the authors reveal how the chromatin remodeler CHD7 and chromatin binding protein 53BP1 regulate distinct DNA repair pathways.
- Magdalena B. Rother
- , Stefania Pellegrino
- & Haico van Attikum
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Article
| Open Access
LSH mediates gene repression through macroH2A deposition
The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription.
- Kai Ni
- , Jianke Ren
- & Kathrin Muegge
Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes