bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–12–17
eightteen papers selected by
Connor Rogerson, University of Cambridge
  1. Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops.
  2. Enhancer-promoter interactions can form independently of genomic distance and be functional across TAD boundaries.
  3. Peak-agnostic high-resolution cis-regulatory circuitry mapping using single cell multiome data.
  4. ASCL1 characterizes adrenergic neuroblastoma via its pioneer function and cooperation with core regulatory circuit factors.
  5. Dynamic chromatin remodeling in cycling human endometrium at single-cell level.
  6. Conserved and divergent gene regulatory programs of the mammalian neocortex.
  7. Thyroid hormone-regulated chromatin landscape and transcriptional sensitivity of the pituitary gland.
  8. Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.
  9. Cell type directed design of synthetic enhancers.
  10. Structure of the complete Saccharomyces cerevisiae Rpd3S-nucleosome complex.
  11. Targeted design of synthetic enhancers for selected tissues in the Drosophila embryo.
  12. CENP-A and CENP-B collaborate to create an open centromeric chromatin state.
  13. Multifaceted SOX2-chromatin interaction underpins pluripotency progression in early embryos.
  14. Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation.
  15. Transcriptional Regulation of FACT Involves Coordination of Chromatin Accessibility and CTCF Binding.
  16. Single-cell analysis of chromatin accessibility in the adult mouse brain.
  17. Epigenetic priming of an epithelial enhancer by p63 and CTCF controls expression of a skin-restricted gene XP33.
  18. BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation.
  1. Nat Commun. 2023 Dec 09. 14(1): 8160
    Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops.
    Daniel Bsteh, Hagar F Moussa, Georg Michlits, Ramesh Yelagandula, Jingkui Wang, Ulrich Elling, Oliver Bell.
      Polycomb Repressive Complexes 1 and 2 (PRC1, PRC2) are conserved epigenetic regulators that promote transcriptional gene silencing. PRC1 and PRC2 converge on shared targets, catalyzing repressive histone modifications. Additionally, a subset of PRC1/PRC2 targets engage in long-range interactions whose functions in gene silencing are poorly understood. Using a CRISPR screen in mouse embryonic stem cells, we found that the cohesin regulator PDS5A links transcriptional silencing by Polycomb and 3D genome organization. PDS5A deletion impairs cohesin unloading and results in derepression of a subset of endogenous PRC1/PRC2 target genes. Importantly, derepression is not linked to loss of Polycomb chromatin domains. Instead, PDS5A removal causes aberrant cohesin activity leading to ectopic insulation sites, which disrupt the formation of ultra-long Polycomb loops. We show that these loops are important for robust silencing at a subset of PRC1/PRC2 target genes and that maintenance of cohesin-dependent genome architecture is critical for Polycomb regulation.
    DOI:  https://doi.org/10.1038/s41467-023-43869-w
  2. Nucleic Acids Res. 2023 Dec 12. pii: gkad1183. [Epub ahead of print]
    Enhancer-promoter interactions can form independently of genomic distance and be functional across TAD boundaries.
    Deevitha Balasubramanian, Pedro Borges Pinto, Alexia Grasso, Séverine Vincent, Hélène Tarayre, Damien Lajoignie, Yad Ghavi-Helm.
      Topologically Associating Domains (TADs) have been suggested to facilitate and constrain enhancer-promoter interactions. However, the role of TAD boundaries in effectively restricting these interactions remains unclear. Here, we show that a significant proportion of enhancer-promoter interactions are established across TAD boundaries in Drosophila embryos, but that developmental genes are strikingly enriched in intra- but not inter-TAD interactions. We pursued this observation using the twist locus, a master regulator of mesoderm development, and systematically relocated one of its enhancers to various genomic locations. While this developmental gene can establish inter-TAD interactions with its enhancer, the functionality of these interactions remains limited, highlighting the existence of topological constraints. Furthermore, contrary to intra-TAD interactions, the formation of inter-TAD enhancer-promoter interactions is not solely driven by genomic distance, with distal interactions sometimes favored over proximal ones. These observations suggest that other general mechanisms must exist to establish and maintain specific enhancer-promoter interactions across large distances.
    DOI:  https://doi.org/10.1093/nar/gkad1183
  3. Nucleic Acids Res. 2023 Dec 12. pii: gkad1166. [Epub ahead of print]
    Peak-agnostic high-resolution cis-regulatory circuitry mapping using single cell multiome data.
    Zidong Zhang, Frederique Ruf-Zamojski, Michel Zamojski, Daniel J Bernard, Xi Chen, Olga G Troyanskaya, Stuart C Sealfon.
      Single same cell RNAseq/ATACseq multiome data provide unparalleled potential to develop high resolution maps of the cell-type specific transcriptional regulatory circuitry underlying gene expression. We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin 'peaks'. These circuit sites outside called peaks are shown to be important cell type specific functional regulatory loci, sufficient to distinguish individual cell types. Analysis of mouse pituitary data identifies a Gata2-circuit for the gonadotrope-enriched disease-associated Pcsk1 gene, which is experimentally validated by reduced gonadotrope expression in a gonadotrope conditional Gata2-knockout model. We present a web accessible human immune cell regulatory circuit resource, and provide CREMA as an R package.
    DOI:  https://doi.org/10.1093/nar/gkad1166
  4. Cell Rep. 2023 Dec 05. pii: S2211-1247(23)01553-X. [Epub ahead of print]42(12): 113541
    ASCL1 characterizes adrenergic neuroblastoma via its pioneer function and cooperation with core regulatory circuit factors.
    Lu Wang, Tze King Tan, Hyoju Kim, Dennis Kappei, Shi Hao Tan, A Thomas Look, Takaomi Sanda.
      Neuroblastoma originates from developing neural crest and can interconvert between the mesenchymal (MES) and adrenergic (ADRN) states, each of which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, the roles of CRC factors in induction and maintenance of specific state are poorly understood. Here, we demonstrate that overexpression of ASCL1, an ADRN CRC factor, in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, initiating the ADRN gene expression program. ASCL1 inhibits the transforming growth factor β-SMAD2/3 pathway but activates the bone morphogenetic protein SMAD1-ID3/4 pathway. ASCL1 and other CRC members potentiate each other's activity, increasing the expression of the original targets and inducing a new set of genes, thereby fully inducing the ADRN program. Our results demonstrate that ASCL1 serves as a pioneer factor and cooperates with CRC factors to characterize the ADRN gene expression program.
    Keywords:  ASCL1; CP: Cancer; chromatin; core regulatory circuit; neuroblastoma; pioneer factor
    DOI:  https://doi.org/10.1016/j.celrep.2023.113541
  5. Cell Rep. 2023 Dec 05. pii: S2211-1247(23)01537-1. [Epub ahead of print]42(12): 113525
    Dynamic chromatin remodeling in cycling human endometrium at single-cell level.
    Pavle Vrljicak, Emma S Lucas, Maria Tryfonos, Joanne Muter, Sascha Ott, Jan J Brosens.
      Estrogen-dependent proliferation followed by progesterone-dependent differentiation of the endometrium culminates in a short implantation window. We performed single-cell assay for transposase-accessible chromatin with sequencing on endometrial samples obtained across the menstrual cycle to investigate the regulation of temporal gene networks that control embryo implantation. We identify uniquely accessible chromatin regions in all major cellular constituents of the endometrium, delineate temporal patterns of coordinated chromatin remodeling in epithelial and stromal cells, and gain mechanistic insights into the emergence of a receptive state through integrated analysis of enriched transcription factor (TF) binding sites in dynamic chromatin regions, chromatin immunoprecipitation sequencing analyses, and gene expression data. We demonstrate that the implantation window coincides with pervasive cooption of transposable elements (TEs) into the regulatory chromatin landscape of decidualizing cells and expression of TE-derived transcripts in a spatially defined manner. Our data constitute a comprehensive map of the chromatin changes that control TF activities in a cycling endometrium at cellular resolution.
    Keywords:  CP: Developmental biology; chromatin accessibility; decidualization; embryo implantation; endometrium; menstrual cycle; transposable elements
    DOI:  https://doi.org/10.1016/j.celrep.2023.113525
  6. Nature. 2023 Dec;624(7991): 390-402
    Conserved and divergent gene regulatory programs of the mammalian neocortex.
    Nathan R Zemke, Ethan J Armand, Wenliang Wang, Seoyeon Lee, Jingtian Zhou, Yang Eric Li, Hanqing Liu, Wei Tian, Joseph R Nery, Rosa G Castanon, Anna Bartlett, Julia K Osteen, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Lei Chang, Keyi Dong, Hannah S Indralingam, Jonathan A Rink, Yang Xie, Michael Miller, Fenna M Krienen, Qiangge Zhang, Naz Taskin, Jonathan Ting, Guoping Feng, Steven A McCarroll, Edward M Callaway, Ting Wang, Ed S Lein, M Margarita Behrens, Joseph R Ecker, Bing Ren.
      Divergence of cis-regulatory elements drives species-specific traits1, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes. We find that conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome. Transposable elements contribute to nearly 80% of the human-specific candidate cis-regulatory elements in cortical cells. Through machine learning, we develop sequence-based predictors of candidate cis-regulatory elements in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Finally, we show that epigenetic conservation combined with sequence similarity helps to uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.
    DOI:  https://doi.org/10.1038/s41586-023-06819-6
  7. Commun Biol. 2023 Dec 11. 6(1): 1253
    Thyroid hormone-regulated chromatin landscape and transcriptional sensitivity of the pituitary gland.
    Young-Wook Cho, Yulong Fu, Chen-Che Jeff Huang, Xuefeng Wu, Lily Ng, Kevin A Kelley, Kristen R Vella, Anders H Berg, Anthony N Hollenberg, Hong Liu, Douglas Forrest.
      Thyroid hormone (3,5,3'-triiodothyronine, T3) is a key regulator of pituitary gland function. The response to T3 is thought to hinge crucially on interactions of nuclear T3 receptors with enhancers but these sites in pituitary chromatin remain surprisingly obscure. Here, we investigate genome-wide receptor binding in mice using tagged endogenous thyroid hormone receptor β (TRβ) and analyze T3-regulated open chromatin using an anterior pituitary-specific Cre driver (Thrbb2Cre). Strikingly, T3 regulates histone modifications and chromatin opening primarily at sites that maintain TRβ binding regardless of T3 levels rather than at sites where T3 abolishes or induces de novo binding. These sites associate more frequently with T3-activated than T3-suppressed genes. TRβ-deficiency blunts T3-regulated gene expression, indicating that TRβ confers transcriptional sensitivity. We propose a model of gene activation in which poised receptor-enhancer complexes facilitate adjustable responses to T3 fluctuations, suggesting a genomic basis for T3-dependent pituitary function or pituitary dysfunction in thyroid disorders.
    DOI:  https://doi.org/10.1038/s42003-023-05546-y
  8. Nature. 2023 Dec;624(7991): 366-377
    Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.
    Hanqing Liu, Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph R Nery, Huaming Chen, Rosa G Castanon, Songpeng Zu, Yang Eric Li, Jacinta Lucero, Julia K Osteen, Antonio Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn O'Connor, Zhanghao Wu, Ion Stoica, Zizhen Yao, Kimberly A Smith, Bosiljka Tasic, Chongyuan Luo, Jesse R Dixon, Hongkui Zeng, Bing Ren, M Margarita Behrens, Joseph R Ecker.
      Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.
    DOI:  https://doi.org/10.1038/s41586-023-06805-y
  9. Nature. 2023 Dec 12.
    Cell type directed design of synthetic enhancers.
    Ibrahim I Taskiran, Katina I Spanier, Hannah Dickmänken, Niklas Kempynck, Alexandra Pančíková, Eren Can Ekşi, Gert Hulselmans, Joy N Ismail, Koen Theunis, Roel Vandepoel, Valerie Christiaens, David Mauduit, Stein Aerts.
      Transcriptional enhancers act as docking stations for combinations of transcription factors (TFs) and thereby regulate spatiotemporal activation of their target genes. It has been a long-standing goal in the field to decode the regulatory logic of an enhancer and to understand the details of how spatiotemporal gene expression is encoded in an enhancer sequence. Here, we show that deep learning models can be used to efficiently design synthetic, cell type specific enhancers, starting from random sequences, and that this optimization process allows for a detailed tracing of enhancer features at single-nucleotide resolution. We evaluate the function of fully synthetic enhancers to specifically target Kenyon cells or glial cells in the fruit fly brain using transgenic animals. We further exploit enhancer design to create "dual-code" enhancers that target two cell types, and minimal enhancers smaller than 50 base pairs that are fully functional. By examining the state space searches towards local optima, we characterise enhancer codes through the strength, combination, and arrangement of TF activator and TF repressor motifs. Finally, we apply the same strategies to successfully design human enhancers, which adhere to similar enhancer rules as Drosophila enhancers. Enhancer design guided by deep learning leads to better understanding of how enhancers work and shows that their code can be exploited to manipulate cell states.
    DOI:  https://doi.org/10.1038/s41586-023-06936-2
  10. Nat Commun. 2023 Dec 08. 14(1): 8128
    Structure of the complete Saccharomyces cerevisiae Rpd3S-nucleosome complex.
    Jonathan W Markert, Seychelle M Vos, Lucas Farnung.
      Acetylation of histones is a key post-translational modification that guides gene expression regulation. In yeast, the class I histone deacetylase containing Rpd3S complex plays a critical role in the suppression of spurious transcription by removing histone acetylation from actively transcribed genes. The S. cerevisiae Rpd3S complex has five subunits (Rpd3, Sin3, Rco1, Eaf3, and Ume1) but its subunit stoichiometry and how the complex engages nucleosomes to achieve substrate specificity remains elusive. Here we report the cryo-EM structure of the complete Rpd3S complex bound to a nucleosome. Sin3 and two copies of subunits Rco1 and Eaf3 encircle the deacetylase subunit Rpd3 and coordinate the positioning of Ume1. The Rpd3S complex binds both trimethylated H3 tails at position lysine 36 and makes multiple additional contacts with the nucleosomal DNA and the H2A-H2B acidic patch. Direct regulation via the Sin3 subunit coordinates binding of the acetylated histone substrate to achieve substrate specificity.
    DOI:  https://doi.org/10.1038/s41467-023-43968-8
  11. Nature. 2023 Dec 12.
    Targeted design of synthetic enhancers for selected tissues in the Drosophila embryo.
    Bernardo P de Almeida, Christoph Schaub, Michaela Pagani, Stefano Secchia, Eileen E M Furlong, Alexander Stark.
      Enhancers control gene expression and play crucial roles in development and homeostasis1-3. However, the targeted de novo design of enhancers with tissue-specific activities has remained challenging. Here, we combine deep learning and transfer learning to design tissue-specific enhancers for five tissues in the Drosophila melanogaster embryo - the central nervous system (CNS), epidermis, gut, muscle, and brain. We first train convolutional neural networks (CNNs) using genome-wide scATAC-seq datasets and then fine-tune the CNNs with smaller-scale data from in vivo enhancer activity assays, yielding models with 25% to 75% positive predictive value according to cross-validation. We designed and experimentally assessed 40 synthetic enhancers (eight per tissue) in vivo, of which 31 (78%) were active and 27 (68%) functioned in the target tissue (100% for CNS and muscle). The strategy to combine genome-wide and small-scale functional datasets by transfer learning is generally applicable and should enable the design of tissue-, cell type-, and cell state-specific enhancers in any system.
    DOI:  https://doi.org/10.1038/s41586-023-06905-9
  12. Nat Commun. 2023 Dec 12. 14(1): 8227
    CENP-A and CENP-B collaborate to create an open centromeric chromatin state.
    Harsh Nagpal, Ahmad Ali-Ahmad, Yasuhiro Hirano, Wei Cai, Mario Halic, Tatsuo Fukagawa, Nikolina Sekulić, Beat Fierz.
      Centromeres are epigenetically defined via the presence of the histone H3 variant CENP-A. Contacting CENP-A nucleosomes, the constitutive centromere associated network (CCAN) and the kinetochore assemble, connecting the centromere to spindle microtubules during cell division. The DNA-binding centromeric protein CENP-B is involved in maintaining centromere stability and, together with CENP-A, shapes the centromeric chromatin state. The nanoscale organization of centromeric chromatin is not well understood. Here, we use single-molecule fluorescence and cryoelectron microscopy (cryoEM) to show that CENP-A incorporation establishes a dynamic and open chromatin state. The increased dynamics of CENP-A chromatin create an opening for CENP-B DNA access. In turn, bound CENP-B further opens the chromatin fiber structure and induces nucleosomal DNA unwrapping. Finally, removal of CENP-A increases CENP-B mobility in cells. Together, our studies show that the two centromere-specific proteins collaborate to reshape chromatin structure, enabling the binding of centromeric factors and establishing a centromeric chromatin state.
    DOI:  https://doi.org/10.1038/s41467-023-43739-5
  13. Science. 2023 Dec 15. 382(6676): eadi5516
    Multifaceted SOX2-chromatin interaction underpins pluripotency progression in early embryos.
    Lijia Li, Fangnong Lai, Xiaoyu Hu, Bofeng Liu, Xukun Lu, Zili Lin, Ling Liu, Yunlong Xiang, Tristan Frum, Michael A Halbisen, Fengling Chen, Qiang Fan, Amy Ralston, Wei Xie.
      Pioneer transcription factors (TFs), such as OCT4 and SOX2, play crucial roles in pluripotency regulation. However, the master TF-governed pluripotency regulatory circuitry was largely inferred from cultured cells. In this work, we investigated SOX2 binding from embryonic day 3.5 (E3.5) to E7.5 in the mouse. In E3.5 inner cell mass (ICM), SOX2 regulates the ICM-trophectoderm program but is dispensable for opening global enhancers. Instead, SOX2 occupies preaccessible enhancers in part opened by early-stage expressing TFs TFAP2C and NR5A2. SOX2 then widely redistributes when cells adopt naive and formative pluripotency by opening enhancers or poising them for rapid future activation. Hence, multifaceted pioneer TF-enhancer interaction underpins pluripotency progression in embryos, including a distinctive state in E3.5 ICM that bridges totipotency and pluripotency.
    DOI:  https://doi.org/10.1126/science.adi5516
  14. Nat Commun. 2023 Dec 07. 14(1): 8101
    Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation.
    Xiao Ge, Haiyan Huang, Keqi Han, Wangjie Xu, Zhaoxia Wang, Qiang Wu.
      CTCF plays an important role in 3D genome organization by adjusting the strength of chromatin insulation at TAD boundaries, where clustered CBS (CTCF-binding site) elements are often arranged in a tandem array with a complex divergent or convergent orientation. Here, using Pcdh and HOXD loci as a paradigm, we look into the clustered CTCF TAD boundaries and find that, counterintuitively, outward-oriented CBS elements are crucial for inward enhancer-promoter interactions as well as for gene regulation. Specifically, by combinatorial deletions of a series of putative enhancer elements in mice in vivo or CBS elements in cultured cells in vitro, in conjunction with chromosome conformation capture and RNA-seq analyses, we show that deletions of outward-oriented CBS elements weaken the strength of long-distance intra-TAD promoter-enhancer interactions and enhancer activation of target genes. Our data highlight the crucial role of outward-oriented CBS elements within the clustered CTCF TAD boundaries in developmental gene regulation and have interesting implications on the organization principles of clustered CTCF sites within TAD boundaries.
    DOI:  https://doi.org/10.1038/s41467-023-43849-0
  15. J Biol Chem. 2023 Dec 08. pii: S0021-9258(23)02566-8. [Epub ahead of print] 105538
    Transcriptional Regulation of FACT Involves Coordination of Chromatin Accessibility and CTCF Binding.
    Peijun Wang, Na Fan, Wanting Yang, Pengbo Cao, Guojun Liu, Qi Zhao, Pengfei Guo, Xihe Li, Xinhua Lin, Ning Jiang, Buhe Nashun.
      Histone chaperone FACT is well known to promote chromatin recovery during transcription. However, the mechanism how FACT regulates genome wide chromatin accessibility and transcription factor binding has not been fully elucidated. Through loss-of-function studies, we show here that FACT component Ssrp1 is required for DNA replication and DNA damage repair, and also essential for progression of cell phase transition and cell proliferation in mouse embryonic fibroblast cells. On the molecular level, absence of the Ssrp1 leads to increased chromatin accessibility, enhanced CTCF binding and a remarkable change in dynamic range of gene expression. Our study thus unequivocally uncovers a unique mechanism by which FACT complex regulates transcription by coordinating genome-wide chromatin accessibility and CTCF binding.
    Keywords:  CTCF; Chromatin accessibility; FACT; Histone chaperone; Ssrp1; Transcription
    DOI:  https://doi.org/10.1016/j.jbc.2023.105538
  16. Nature. 2023 Dec;624(7991): 378-389
    Single-cell analysis of chromatin accessibility in the adult mouse brain.
    Songpeng Zu, Yang Eric Li, Kangli Wang, Ethan J Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Lin Lin, Qian Yang, Seoyeon Lee, Bin Li, Samantha Kuan, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, Michael Nunn, Kimberly A Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng, Zihan Wang, Jingbo Shang, M Margarita Behrens, Joseph R Ecker, Allen Wang, Sebastian Preissl, Bing Ren.
      Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1-4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs-specifically, those identified from a subset of cortical excitatory neurons-are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains.
    DOI:  https://doi.org/10.1038/s41586-023-06824-9
  17. Cell Death Discov. 2023 Dec 08. 9(1): 446
    Epigenetic priming of an epithelial enhancer by p63 and CTCF controls expression of a skin-restricted gene XP33.
    Artem Smirnov, Anna Maria Lena, Giulia Tosetti, Xue Yang, Angela Cappello, Manuela Helmer Citterich, Gerry Melino, Eleonora Candi.
      The transcription factor p63 is a renowned master regulator of gene expression of stratified epithelia. While multiple proteins have been identified as p63 bona fide targets, little is known about non-coding RNAs (ncRNAs) whose transcription is controlled by p63. Here, we describe a skin-specific non-coding RNA XP33 as a novel target of p63. XP33 levels are increased during keratinocyte differentiation in vitro, while its depletion results in decreased expression of late cornified gene LCE2D. By using publicly available multi-omics data, we show that CTCF and p63 establish an epithelial enhancer to prime XP33 transcription in a tissue-restricted manner. XP33 promoter and enhancer form a chromatin loop exclusively in keratinocytes but not in other cell types. Moreover, the XP33 enhancer is occupied by differentiation-specific factors that control XP33 transcription. Altogether, we identify a tissue-specific non-coding RNA whose expression is epigenetically regulated by p63 and CTCF.
    DOI:  https://doi.org/10.1038/s41420-023-01716-3
  18. Development. 2023 Dec 08. pii: dev.202110. [Epub ahead of print]
    BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation.
    Rachel E Musa, Kaitlyn L Lester, Gabrielle A Quickstad, Sara Vardabasso, Trevor V Shumate, Ryan T Salcido, Kai Ge, Karl B Shpargel.
      Cornelia de Lange syndrome (CdLS) is a congenital disorder featuring facial dysmorphism, postnatal growth deficits, cognitive disability, and upper limb abnormalities. CdLS is genetically heterogeneous with cases arising from mutation of BRD4, a bromodomain protein that binds and reads acetylated histones. In this study we have modeled CdLS facial pathology through mouse neural crest cell (NCC) specific mutation of BRD4 to characterize cellular and molecular function in craniofacial development. Mice with BRD4 NCC loss of function died at birth with severe facial hypoplasia, cleft palate, mid-facial clefting, and exencephaly. Following migration, BRD4 mutant NCCs initiated RUNX2 expression for differentiation to osteoblast lineages but failed to induce downstream RUNX2 targets required for lineage commitment. BRD4 bound to active enhancers to regulate expression of osteogenic transcription factors and extracellular matrix components integral for bone formation. RUNX2 physically interacts with a carboxy-terminal (C-terminal) domain in the long isoform of BRD4, can co-occupy osteogenic enhancers, and this association is required for RUNX2 recruitment and appropriate osteoblast differentiation. We conclude that BRD4 controls facial bone development through osteoblast enhancer regulation of the RUNX2 transcriptional program.
    Keywords:  BRD4; Cornelia de Lange syndrome; Craniofacial; Histone acetylation reader; Neural crest
    DOI:  https://doi.org/10.1242/dev.202110
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