Featured
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| Open AccessDOT1L 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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Article
| Open AccessReference panel guided topological structure annotation of Hi-C data
Predicting topological structures from Hi-C data provides insight into comprehending gene expression and regulation. Here, the authors present RefHiC, an attention-based deep learning framework that leverages a reference panel of Hi-C datasets to assist topological structure annotation from a given study sample.
- Yanlin Zhang
- & Mathieu Blanchette
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Article
| Open AccessA unified computational framework for single-cell data integration with optimal transport
Integrating heterogeneous single-cell multi-omics as well as spatially resolved transcriptomic data remains a major challenge. Here the authors report a unified single-cell data integration framework using an unbalanced optimal transport-based deep network.
- Kai Cao
- , Qiyu Gong
- & Lin Wan
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| Open AccessPCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment
Here the authors show that a Polycomb Repressive Complex 1 (PRC1) containing PCGF1 prevents excessive loading of transcriptional activators and chromatin remodelers on nascent DNA, allowing proper deposition of nucleosomes immediately after the passage of the DNA replication fork to optimize downstream chromatin configurations in hematopoietic stem and progenitor cells (HSPCs).
- Junichiro Takano
- , Shinsuke Ito
- & Tomokatsu Ikawa
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| Open AccessChromatin 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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Article
| Open AccessStructural basis of RNA polymerase II transcription on the chromatosome containing linker histone H1
The mechanism by which RNAPII transcribes the DNA in the chromatosome with H1 has remained enigmatic. Here the authors present the cryo-EM structures of the RNAPII-chromatosome complexes, and explain how RNAPII is regulated by H1 in chromatin.
- Rina Hirano
- , Haruhiko Ehara
- & Hitoshi Kurumizaka
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Article
| Open AccessPICH 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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| Open AccessThe 3D enhancer network of the developing T cell genome is shaped by SATB1
Here the authors analyze the 3D genome structure of murine thymocytes and show that SATB1, a predominantly T-cell specific protein, helps to establish a regulatory, finer-scale organizational layer built upon a pre-existing chromatin scaffold mediated by other architectural proteins, such as CTCF.
- Tomas Zelenka
- , Antonios Klonizakis
- & Charalampos Spilianakis
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| Open AccessHi-TrAC reveals division of labor of transcription factors in organizing chromatin loops
It is currently not clear how architectural proteins orchestrate chromatin looping at different scales of genome organisation. Here the authors report Hi-TrAC as a proximity ligation-free method to profile genome-wide chromatin interactions at single nucleosome resolution among regulatory elements.
- Shuai Liu
- , Yaqiang Cao
- & Keji Zhao
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Article
| Open AccessEnhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity
The role of enhancer de-regulation in anti-tumor immunity remains to be explored. Here, the authors suggest that ablation of MLL3 and MLL4, two enhancer-associated H3K4 monomethyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response.
- Hanhan Ning
- , Shan Huang
- & Deqing Hu
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Article
| Open AccessA 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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Article
| Open AccessDecoding 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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Article
| Open AccessMYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.
- Hiroki Takahashi
- , Ge Yang
- & Juro Sakai
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Article
| Open AccessHuman centromere repositioning activates transcription and opens chromatin fibre structure
In this study, using a human neocentromere as a model, the authors show that centromeres have a special chromatin structure. Centromere repositioning triggers transcriptional activation, epigenetic remodelling and chromatin fibre decompaction.
- Catherine Naughton
- , Covadonga Huidobro
- & Nick Gilbert
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| Open AccessChromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers
Here the authors show the identity of CD4 + CD8 + double-positive (DP) thymocytes changes upon loss of chromatin organizer Satb1, which controls the expression of cell identity genes by regulating super-enhancers via 3D genome architecture.
- Delong Feng
- , Yanhong Chen
- & Bingtao Hao
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Article
| Open AccessVAL1 acts as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC
Cold-induced silencing of Arabidopsis FLC requires the binding of VAL1 to an intronic motif. Here, the authors show that ASAP and PRC1, two interacting partner complexes of VAL1, mediate co-transcriptional repression and chromatin modulation to effectively co-ordinate different steps in FLC silencing.
- Pawel Mikulski
- , Philip Wolff
- & Caroline Dean
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Article
| Open AccessDeciphering multi-way interactions in the human genome
Mapping higher order chromatin architecture is important. Here the authors use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organisation; they use hypergraph theory for data representation and analysis, and apply this to different cell types.
- Gabrielle A. Dotson
- , Can Chen
- & Indika Rajapakse
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| Open AccessDominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm
Silencing of endogenous retroviruses is crucial for maintaining transcriptional and genomic integrity of cells and is maintained by histone H3K9 methylation and/or DNA methylation in various cell types. Here the authors show that loss of DNA methyltransferase DNMT1 in endoderm results in ERV derepression while H3K9me3 is unaltered.
- Zeyang Wang
- , Rui Fan
- & Gunnar Schotta
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| Open AccessMultimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression
Diabetic kidney disease leads to changes in glucose metabolism and inflammation. Here the authors use multimodal single cell sequencing to show that this disease leads to reduced accessibility of glucocorticoid receptor binding sites in the proximal tubule and increased gluconeogenesis.
- Parker C. Wilson
- , Yoshiharu Muto
- & Benjamin D. Humphreys
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| Open AccessNODULIN HOMEOBOX is required for heterochromatin homeostasis in Arabidopsis
Arabidopsis NDX was previously reported as a regulator of euchromatic gene expression. Here the authors show that NDX functions at pericentromeric regions and regulates heterochromatin homeostasis by controlling siRNA production and non-CG methylation.
- Zsolt Karányi
- , Ágnes Mosolygó-L
- & Lóránt Székvölgyi
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| Open AccessNucleosome-directed replication origin licensing independent of a consensus DNA sequence
Most eukaryotes do not use a consensus DNA sequence as binding sites for the origin recognition complex (ORC) to initiate DNA replication, however budding yeast do. Here the authors show S. cerevisiae ORC can bind nucleosomes near nucleosome-free regions and recruit replicative helicases to form a pre-replication complex independent of the DNA sequence.
- Sai Li
- , Michael R. Wasserman
- & Shixin Liu
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Article
| Open AccessXPC–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 AccessTranscription-coupled and epigenome-encoded mechanisms direct H3K4 methylation
Methylation of histone H3 lysine 4 is associated with transcription. Here the authors describe three Arabidopsis methyltransferases that direct H3K4me1 and propose that one methyltransferase works co-transcriptionally while the others are recruited to genomic and epigenomic features.
- Satoyo Oya
- , Mayumi Takahashi
- & Soichi Inagaki
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| Open AccessPRC1-mediated epigenetic programming is required to generate the ovarian reserve
In humans, the ovarian reserve is maintained over decades by meiotic arrest of oocytes. Here the authors show that Polycomb Repressive Complex 1 (PRC1)-mediated epigenetic programming is essential for formation of ovarian reserve and thus female reproductive lifespan.
- Mengwen Hu
- , Yu-Han Yeh
- & Satoshi H. Namekawa
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Article
| Open AccessPCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression
Variant Polycomb complexes can have tissue-specific roles during development. Here they show that PCGF6 controls lineage-specification in human PSCs by promoting neuroectoderm differentiation and repressing mesendoderm differentiation via distinct downstream targets.
- Xianchun Lan
- , Song Ding
- & Wei Jiang
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Article
| Open AccessInteraction between transcribing RNA polymerase and topoisomerase I prevents R-loop formation in E. coli
In E. coli, disruption of TopoI and RNAP interaction decreases cells viability and leads to hypernegative DNA supercoiling and R loops accumulation. TopoI and DNA gyrase bind around transcription units and TopoI recognizes cleavage sites by a specific motif and negative supercoiling.
- Dmitry Sutormin
- , Alina Galivondzhyan
- & Konstantin Severinov
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Article
| Open AccessHistone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes
DNMT3A is known to methylate DNA at histone H3 lysine 36 (H3K36me3)-marked transcriptionally active regions in mouse oocytes. Here the authors show that DNMT3A is also guided by H3K36me2 to methylate broad domains in genic and intergenic loci, as well as on the X chromosome. These two histone marks together comprise the minimal chromatin signature for global DNA methylation in mouse oocytes.
- Seiichi Yano
- , Takashi Ishiuchi
- & Hiroyuki Sasaki
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Article
| Open AccessTRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
Gonadal fate in mammals is determined during embryogenesis and is actively maintained in adulthood. This study shows that E3-SUMO ligase activity of TRIM28 is required for ovarian identity maintenance and testicular-specific gene repression in mouse adult ovary; in its absence, ovarian granulosa cells transdifferentiate to Sertoli cells.
- Moïra Rossitto
- , Stephanie Déjardin
- & Francis Poulat
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Article
| Open AccessHSF1 phosphorylation establishes an active chromatin state via the TRRAP–TIP60 complex and promotes tumorigenesis
Here the authors show phosphorylation of heat shock factor 1 (HSF1) at S419 via the chromatin-bound kinase PLK1, promotes HSF1 recruitment of histone acetyltransferases and histone acetylation reader proteins TRIM33 and TRIM24, which actually also execute histone H2BK120 mono-ubiquitination at target genes. Furthermore, HSF1 phosphorylation has an impact on melanoma cell proliferation.
- Mitsuaki Fujimoto
- , Ryosuke Takii
- & Akira Nakai
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Article
| Open AccessDysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis
Vascular dysfunction is associated with ageing and chronic diseases, but its role in lung repair and fibrosis is unclear. Here, the authors show that the endothelial transcription factor ERG is a mediator of vascular repair whose function declines in aged lungs resulting in sustained fibrosis
- Nunzia Caporarello
- , Jisu Lee
- & Giovanni Ligresti
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Article
| Open AccessPostmitotic differentiation of human monocytes requires cohesin-structured chromatin
How chromatin structure and gene accessibility changes during monocyte differentiation is not clearly defined. Here the authors characterize the chromatin changes during macrophage or dendritic cell maturation from monocytes and the dependence of this upon cohesin and CTCF.
- Julia Minderjahn
- , Alexander Fischer
- & Michael Rehli
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Article
| Open AccessEtv2 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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Article
| Open AccessBromodomain factor 5 is an essential regulator of transcription in Leishmania
Leishmania use large (5–10 kb) transcriptional start regions, where the chromatin is highly enriched for acetylated histones, to drive the expression of polycistronic gene arrays. Here the authors show bromodomain-containing protein BDF5 is enriched at transcriptional start sites and its depletion leads to cell death in vitro and in murine infections, and they identify its interactors.
- Nathaniel G. Jones
- , Vincent Geoghegan
- & Jeremy C. Mottram
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Article
| Open AccessLoop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding
Two main mechanisms have been proposed to shape 3D genome architecture - loop extrusion and phase separation. Here the authors combine these mechanisms in polymer models in a manner that best fits 3D genome, based on both Hi-C and super-resolution locus imaging data, proposing that these two physical processes can indeed coexist simultaneously within cells to define loops and TADs.
- Mattia Conte
- , Ehsan Irani
- & Mario Nicodemi
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| Open AccessChromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA
Here the authors used single-molecule imaging and manipulation to study the mechanical effects of transcription factor Sox2 co-condensation with DNA and chromatin. They found that Sox2 condensates exert a high level of mechanical stress on DNA, but this stress is dramatically attenuated by nucleosomes assembled on the DNA.
- Tuan Nguyen
- , Sai Li
- & Shixin Liu
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Article
| Open AccessCD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
Understanding CD8 + T cell response to immune checkpoint blockade at the molecular level is important for the design of more efficient cancer immune therapies. Authors show here that the histone lysine methyltransferase Suv39h1 controls the transcriptional programs that determine the functionality of CD8 + T cells and Suv39h1 inhibition may potentiate anti-PD-1 therapy of melanomas.
- Leticia Laura Niborski
- , Paul Gueguen
- & Eliane Piaggio
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Article
| Open AccessSatellite 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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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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Article
| Open AccessSex-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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Article
| Open AccessSMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters
SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.
- Yanjun Zhang
- , Yuan Fang
- & Dong Fang
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Article
| Open AccessLarge-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation
Cohesin complex is essential for transcriptional regulation and chromosome folding. Here the authors provide a large-scale multi-omics analysis suggesting that cohesin bound on gene bodies has a specific role in transcriptional regulation.
- Jiankang Wang
- , Masashige Bando
- & Ryuichiro Nakato
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Article
| Open AccessDynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model
Here the authors provide a multi-omic study of the nucleosome landscape in LNCaP cells and observe nine functional nucleosome states each with characteristic nucleosome footprints. Upon androgen stimulation, they observed changes in these nucleosome states accompanied by changes in binding and function of pioneer factors, including GATA2.
- Tianbao Li
- , Qi Liu
- & Victor X. Jin
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Article
| Open AccessJMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation
Here the authors demonstrate that TGFβ drives multi-enhancer contacts and ultimately gene activation during neuronal commitment, and that this requires the intrinsically disordered region (IDR) of the histone demethylase JMJD3 likely through its role in promoting phase-separated biomolecular condensates.
- Marta Vicioso-Mantis
- , Raquel Fueyo
- & Marian A. Martínez-Balbás
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Article
| Open AccessIntegrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction
Here they perform an integrative analysis of the epigenetic landscape of human pluripotent stem cell hematopoietic differentiation and show that JUNB is an indispensable transcription factor for hemogenic endothelium development.
- Xia Chen
- , Peiliang Wang
- & Jie Na
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Article
| Open AccessBRD4 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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Article
| Open AccessSingle-cell chromatin profiling of the primitive gut tube reveals regulatory dynamics underlying lineage fate decisions
The primitive gut tube gives rise to all major internal organs, while underlying regulatory mechanisms are unclear. Here, the authors analyze its chromatin landscape at the single-cell level and define the epigenetic regulation of lineage fate decisions and plasticity in organ development and homeostasis.
- Ryan J. Smith
- , Hongpan Zhang
- & Tae-Hee Kim
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Article
| Open AccessReconstruct high-resolution 3D genome structures for diverse cell-types using FLAMINGO
High-resolution reconstruction of spatial chromosome organisation is in demand. Here the authors report FLAMINGO, for reconstructing high-resolution 3D Genome Organisation from HiC data which they use to generate both 5 kb and 1 kb-resolution 3D chromosomal structures for the human genome.
- Hao Wang
- , Jiaxin Yang
- & Jianrong Wang
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Article
| Open AccessRegulation 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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Article
| Open AccessChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.
- Lorna A. Farrelly
- , Shuangping Zheng
- & Ian Maze