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| Open AccessEpigenetic 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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Article
| Open AccessHdac1 and Hdac2 regulate the quiescent state and survival of hair-follicle mesenchymal niche
Cell division and stem cell maintenance are tightly linked. Here they show that in the hair follicle an epigenetic mechanism maintains mesenchymal niche dormancy in a highly proliferative microenvironment while repurposing mitogenic signaling to orchestrate the hair cycle clock.
- Hadas Sibony-Benyamini
- , Emil Aamar
- & David Enshell-Seijffers
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Article
| Open AccessGetting personal with epigenetics: towards individual-specific epigenomic imputation with machine learning
The authors present eDICE, an attention-based model that enables accurate imputation of missing portions of the observed epigenetic landscape, and show that eDICE can be used to predict individualspecific epigenomic variation in the EN-TEx dataset.
- Alex Hawkins-Hooker
- , Giovanni Visonà
- & Gabriele Schweikert
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Article
| Open AccessThe 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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Article
| Open AccessMolecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome
The mechanism by which the chromatinized HBV genome is transcribed remains poorly understood. In this study, Liu et al. demonstrate how HBx exploits Spindlin1, a histone methylation reader, to overcome heterochromatin barriers and enhance HBV transcription from the cccDNA minichromosome.
- Wei Liu
- , Qiyan Yao
- & Haitao Li
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Article
| Open AccessEzh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.
- Julie Rondeaux
- , Déborah Groussard
- & Sylvain Fraineau
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Article
| Open AccessMOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters
Here the authors show that epigenetic regulation through the histone acetyltransferase MOF and the acetylation of histone H4 lysine 16 affect essential functions in the mitochondria and primary cilia. This regulation is important to promote epidermal differentiation and hair follicle formation.
- Dongmei Wang
- , Haimin Li
- & Rui Yi
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| Open AccessEngineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.
- Kadir Buyukcelebi
- , Xintong Chen
- & Mazhar Adli
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Article
| Open AccessA 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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Article
| Open AccessThe cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells
Niemann-Pick type C disease is characterized by deficiency of the endolysosomal cholesterol transporter NPC1. Here, the authors show in Npc1−/− mice that loss of NPC1 impairs oligodendrocyte lineage cell differentiation and developmental myelination through perturbed epigenetic regulation.
- Thaddeus J. Kunkel
- , Alice Townsend
- & Andrew P. Lieberman
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Article
| Open AccessSingle cohesin molecules generate force by two distinct mechanisms
Cohesin protein complex is a molecular machine that extrudes DNA loops. Here, authors show that bending of the molecule’s long coiled coils is driven by thermal fluctuations and engagement of ATPase domains uses ATP energy to generate strong force.
- Georgii Pobegalov
- , Lee-Ya Chu
- & Maxim I. Molodtsov
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Article
| Open AccessASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair
Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.
- Corina Maritz
- , Reihaneh Khaleghi
- & Hanspeter Naegeli
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Article
| Open AccessDissecting 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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Article
| Open AccessHistone exchange sensors reveal variant specific dynamics in mouse embryonic stem cells
Eviction of histones from nucleosomes and their exchange with newly synthesized or alternative variants is a central epigenetic determinant. Here the authors implement a molecular sensor that reports on steady-state exchange of histones in mESC and mice revealing dependency between deposition of histone variant H3.3 and exchange of H3.1 and H2B in both open and closed chromatin.
- Marko Dunjić
- , Felix Jonas
- & Yonatan Stelzer
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Article
| Open AccessSingle-cell transcriptomics and epigenomics unravel the role of monocytes in neuroblastoma bone marrow metastasis
The bone marrow is a common site of metastasis for neuroblastoma patients. Here, the authors perform single cell RNA-seq and ATAC-seq of bone marrow aspirates from 16 subjects and show conservation of tumor cell plasticity in metastases and identify tumor-to-bone marrow cell signals that trigger tumor promoting monocytes.
- Irfete S. Fetahu
- , Wolfgang Esser-Skala
- & Sabine Taschner-Mandl
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Article
| Open AccessChromatin remodeling by Pol II primes efficient Pol III transcription
Transcription of RNA polymerase II is coupled with remodeling of chromatin. This study reports that transcription of RNA polymerase II is also required to prime and maintain nucleosome depletion at RNA polymerase III loci.
- Carlo Yague-Sanz
- , Valérie Migeot
- & Damien Hermand
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Article
| Open AccessChemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid
Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.
- Severin Lechner
- , Raphael R. Steimbach
- & Bernhard Kuster
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Article
| Open AccessDynamic 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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Article
| Open AccessImpaired histone inheritance promotes tumor progression
Here the authors show disturbing parental histone inheritance in cancer cells drives tumor progression by reprogramming the epigenetic profile and conferring fitness advantages to some of the newly emerged subclones.
- Congcong Tian
- , Jiaqi Zhou
- & Haiyun Gan
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Article
| Open AccessA crucial role for dynamic expression of components encoding the negative arm of the circadian clock
A screen for clock mutants uncovered a conserved novel auxiliary NuA4 histone acetylase complex, containing orthologs of BRD-8 and BYE-1, needed for maintaining the timely Negative Element expression required for sustaining a normal circadian rhythm.
- Bin Wang
- , Xiaoying Zhou
- & Jay C. Dunlap
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Article
| Open AccessACL and HAT1 form a nuclear module to acetylate histone H4K5 and promote cell proliferation
Xu et al. showed that a histone acetyltransferase interacts with an acetyl-CoA synthetic enzyme for histone acetylation to stimulate gene expression and endosperm cell division, pointing to a mechanism coupling energy metabolism to epigenetics.
- Qiutao Xu
- , Yaping Yue
- & Dao-Xiu Zhou
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Article
| Open AccessCryo-EM structure of the Saccharomyces cerevisiae Rpd3L histone deacetylase complex
The Rpd3L HDAC complex is an ancient chromatin-modifying complex found in diverse eukaryotes. Here, authors describe the cryo-EM structure of the yeast complex and show that key features are preserved in the human complex.
- Avinash B. Patel
- , Jinkang Qing
- & Yuan He
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Article
| Open AccessThe 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
| Open AccessMechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex
SIN3B is a histone deacetylase part of the holo-SIN3 complex. Here by cryo-electron microscopy we unveil the assembly, activation, specificity, and substrate recognition of the human SIN3B histone deacetylase complex.
- Mandy S. M. Wan
- , Reyhan Muhammad
- & Claudio Alfieri
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| Open AccessDependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis
Transcriptional dysregulation contributes to tumor progression. Here the authors show that transcriptional complex NELF interacts with SLUG, and co-opts KAT2B, to promote the expression of epithelial-mesenchymal transition (EMT) and stemness-associated genes in breast cancer.
- Jieqiong Zhang
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
| Open AccessThe AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner
rAAV vectors vary in their effectiveness between species, making it difficult to predict clinical outcomes. Here authors show that AAV capsid proteins influence the vector epigenomic state in cells, and that a single amino acid change in the vector can alter the vector epigenome and hence transgene expression levels between species.
- Adriana Gonzalez-Sandoval
- , Katja Pekrun
- & Mark A. Kay
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Article
| Open AccessHistone 4 lysine 5/12 acetylation enables developmental plasticity of Pristionchus mouth form
Developmental plasticity allows organisms to match traits to their environment, however, there are few known molecular mechanisms underlying such plasticity. Here, the authors show that feeding morphs in adult Pristionchus nematodes are set during a critical window in juveniles and identify H4K5/12ac as the environmental information carrier.
- Michael S. Werner
- , Tobias Loschko
- & Ralf J. Sommer
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Article
| Open AccessEnhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation
Heterotopic ossification is a disorder characterized by the transformation of soft tissue to bone. In this study the authors report heterotopic ossification in a child caused by enhancer hijacking at the ARHGAP36 gene, the ectopic activation by an enhancer that it not its own.
- Uirá Souto Melo
- , Jerome Jatzlau
- & Malte Spielmann
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Article
| Open AccessMOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
Altered transcriptional machinery promotes aberrant self-renewal of non-stem hematopoietic progenitors. Here the authors show that AF10 fusion proteins cause aberrant self-renewal via ENL, which promotes leukemic transformation by binding to MOZ/MORF lysine acetyltransferases
- Yosuke Komata
- , Akinori Kanai
- & Akihiko Yokoyama
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Article
| Open AccessMYC reshapes CTCF-mediated chromatin architecture in prostate cancer
The functional link between MYC and CTCF in prostate cancer remains to be investigated. Here, the authors highlight the role of MYC in rewiring chromatin architecture by interacting with CTCF protein.
- Zhao Wei
- , Song Wang
- & Haiyang Guo
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Article
| Open AccessCombinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3
Congenital limb defects are often associated with genomic rearrangements. Here they provide insights into the molecular mechanism underlying SHFM3-associated structural variations, offering a conceptual framework for how genomic rearrangements can alter gene expression and cause disease.
- Giulia Cova
- , Juliane Glaser
- & Stefan Mundlos
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Article
| Open AccessBRD9-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 AccessPhosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence
Little is known about the role of glycolysis in cellular senescence. Here, authors report that glycolysis-derived serine biosynthesis activates PKM2 to phosphorylate histone H3T11, prevent cell senescence, and promote healthy aging.
- Yinsheng Wu
- , Lixu Tang
- & Xilan Yu
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Article
| Open AccessDifferent NIPBL requirements of cohesin-STAG1 and cohesin-STAG2
NIPBL is considered the cohesin loader. Here, the authors report that a drastic reduction of NIPBL levels reduces chromatin-bound cohesin-STAG2 genome wide while cohesin-STAG1 increases and can still be found at CTCF-bound sites but cannot form loops.
- Dácil Alonso-Gil
- , Ana Cuadrado
- & Ana Losada
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Article
| Open AccessCTCF 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 AccessAdaptive 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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Article
| Open AccessA CpG island-encoded mechanism protects genes from premature transcription termination
Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
- Amy L. Hughes
- , Aleksander T. Szczurek
- & Robert J. Klose
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Article
| Open AccessEpigenetic control of cellular crosstalk defines gastrointestinal organ fate and function
Mesenchymal-epithelial crosstalk plays a key role in gut development and stem cell homeostasis, though underlying mechanisms are still unclear. Here, the authors demonstrate that mesenchymal Polycomb Repressive Complex 2 controls niche signals for gut epithelial fate and growth.
- Ryan J. Smith
- , Minggao Liang
- & Tae-Hee Kim
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Article
| 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 AccessHSFA1a modulates plant heat stress responses and alters the 3D chromatin organization of enhancer-promoter interactions
Here the authors show genome-wide chromatin changes and transcriptional reprogramming occur in response to heat stress in tomato, leading to the transient formation of promoter-enhancer contacts to drive the expression of heat-stress responsive genes. Furthermore, they show chromatin spatial reorganization requires HSFA1a, a transcription factor (TF) essential for heat stress tolerance in tomato.
- Ying Huang
- , Jing An
- & Moussa Benhamed
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Article
| Open AccessRSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells
Pluripotency is coordinated at multiple levels of gene expression. Here the authors show that ribosome biogenesis is tightly regulated in embryonic stem cells (ESC) to control the translation of transcription and chromatin factors and dictate ESC fate.
- Sébastien Durand
- , Marion Bruelle
- & Mathieu Gabut
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Article
| Open AccessLow input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution
Here the authors present the low input capture Hi-C (liCHi-C) method, a cost-effective, flexible method to map and robustly compare promoter interactomes at high resolution. liCHi-C identifies new disease-associated genes and structural variants to ultimately illuminate their pathogenic effects.
- Laureano Tomás-Daza
- , Llorenç Rovirosa
- & Biola M. Javierre
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Article
| Open AccessChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs
Methods connecting genes to their cis-regulatory elements usually requires millions of input cells. Here the authors combine proximity ligation in ChIA-PET and transposase accessibility in ATAC-seq, reporting ChIATAC, to map interactions between open chromatin loci in low numbers of input cells.
- Haoxi Chai
- , Harianto Tjong
- & Yijun Ruan
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Article
| Open AccessChanges in PRC1 activity during interphase modulate lineage transition in pluripotent cells
Changes in Polycomb repression during interphase transition modulate the ability of pluripotent cells to enter cell differentiation.
- Helena G. Asenjo
- , María Alcazar-Fabra
- & David Landeira
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Article
| Open AccessThe SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators
Here the authors establish the SPOC domain as a universal reader of the RNA Pol II CTD code and a versatile reader of phosphoserine marks found in co- and post-transcriptional regulators such as m6A writer and reader proteins.
- Lisa-Marie Appel
- , Vedran Franke
- & Dea Slade
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Article
| Open AccessSimultaneous profiling of histone modifications and DNA methylation via nanopore sequencing
The interplay between histone modifications and DNA methylation plays a crucial role in establishing and maintaining the epigenomic landscape. Here, the authors develop a nanopore sequencing based method for mapping histone modifications and DNA methylation from native, long, single DNA molecules.
- Xue Yue
- , Zhiyuan Xie
- & Yimeng Yin
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Article
| Open AccessEngineering inducible biomolecular assemblies for genome imaging and manipulation in living cells
Imaging non-repetitive loci in living cells remains challenging. Here, the authors engineered an inducible system whereby biomolecular assemblies can be guided to specific genomic loci by a nuclease-defective Cas9, allowing the simultaneous imaging and manipulation of the loci.
- Qin Peng
- , Ziliang Huang
- & Yingxiao Wang
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Article
| Open AccessStructural insights into p300 regulation and acetylation-dependent genome organisation
Here the authors use structural analyses to show that an intrinsically disordered transcription activation domain in the oncogene BRD4-NUT binds to and activates p300. This in-turn drives formation of higher-order, acetylation-dependent chromatin condensates.
- Ziad Ibrahim
- , Tao Wang
- & Daniel Panne
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| Open AccessFunctional 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