bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023‒09‒03
seventeen papers selected by
Connor Rogerson, University of Cambridge
  1. Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models.
  2. Eomes restricts Brachyury functions at the onset of mouse gastrulation.
  3. Transposable elements as tissue-specific enhancers in cancers of endodermal lineage.
  4. Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects.
  5. HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.
  6. Optimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements.
  7. scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.
  8. Competition between transcription and loop extrusion modulates promoter and enhancer dynamics.
  9. DAXX safeguards heterochromatin formation in embryonic stem cells.
  10. Mettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue.
  11. The Swi-Snf chromatin remodeling complex mediates gene repression through metabolic control.
  12. Loss of BRD4 induces cell senescence in HSC/HPCs by deregulating histone H3 clipping.
  13. Changes in adenoviral chromatin organization precede early gene activation upon infection.
  14. Chromatin remodeling of histone H3 variants by DDM1 underlies epigenetic inheritance of DNA methylation.
  15. Control of murine brown adipocyte development by GATA6.
  16. A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation.
  17. Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation.
  1. Nucleic Acids Res. 2023 Aug 31. pii: gkad693. [Epub ahead of print]
    Widespread effects of DNA methylation and intra-motif dependencies revealed by novel transcription factor binding models.
    Jan Grau, Florian Schmidt, Marcel H Schulz.
      Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that show a binding behaviour associated with DNA methylation. Overall, we find that the presence of CpG methylation decreases the likelihood of binding for the majority of methylation-associated TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding. We illustrate that the novel methylation-aware TF binding models allow to predict differential ChIP-seq peaks and improve the genome-wide analysis of TF binding. Our work indicates that simplistic models that neglect the effect of DNA methylation on DNA binding may lead to systematic underperformance for methylation-associated TFs.
    DOI:  https://doi.org/10.1093/nar/gkad693
  2. Dev Cell. 2023 Aug 22. pii: S1534-5807(23)00396-9. [Epub ahead of print]
    Eomes restricts Brachyury functions at the onset of mouse gastrulation.
    Katrin M Schüle, Jelena Weckerle, Simone Probst, Alexandra E Wehmeyer, Lea Zissel, Chiara M Schröder, Mehmet Tekman, Gwang-Jin Kim, Inga-Marie Schlägl, Sagar, Sebastian J Arnold.
      Mammalian specification of mesoderm and definitive endoderm (DE) is instructed by the two related Tbx transcription factors (TFs) Eomesodermin (Eomes) and Brachyury sharing partially redundant functions. Gross differences in mutant embryonic phenotypes suggest specific functions of each TF. To date, the molecular details of separated lineage-specific gene regulation by Eomes and Brachyury remain poorly understood. Here, we combine mouse embryonic and stem-cell-based analyses to delineate the non-overlapping, lineage-specific transcriptional activities. On a genome-wide scale, binding of both TFs overlaps at promoters of target genes but shows specificity for distal enhancer regions that is conferred by differences in Tbx DNA-binding motifs. The unique binding to enhancer sites instructs the specification of anterior mesoderm (AM) and DE by Eomes and caudal mesoderm by Brachyury. Remarkably, EOMES antagonizes BRACHYURY gene regulatory functions in coexpressing cells during early gastrulation to ensure the proper sequence of early AM and DE lineage specification followed by posterior mesoderm derivatives.
    Keywords:  Brachyury; Eomes; T-box transcription factors; chromatin accessibility; endoderm; lineage specification; mesoderm; mouse gastrulation; transcriptional control
    DOI:  https://doi.org/10.1016/j.devcel.2023.07.023
  3. Nat Commun. 2023 Sep 01. 14(1): 5313
    Transposable elements as tissue-specific enhancers in cancers of endodermal lineage.
    Konsta Karttunen, Divyesh Patel, Jihan Xia, Liangru Fei, Kimmo Palin, Lauri Aaltonen, Biswajyoti Sahu.
      Transposable elements (TE) are repetitive genomic elements that harbor binding sites for human transcription factors (TF). A regulatory role for TEs has been suggested in embryonal development and diseases such as cancer but systematic investigation of their functions has been limited by their widespread silencing in the genome. Here, we utilize unbiased massively parallel reporter assay data using a whole human genome library to identify TEs with functional enhancer activity in two human cancer types of endodermal lineage, colorectal and liver cancers. We show that the identified TE enhancers are characterized by genomic features associated with active enhancers, such as epigenetic marks and TF binding. Importantly, we identify distinct TE subfamilies that function as tissue-specific enhancers, namely MER11- and LTR12-elements in colon and liver cancers, respectively. These elements are bound by distinct TFs in each cell type, and they have predicted associations to differentially expressed genes. In conclusion, these data demonstrate how different cancer types can utilize distinct TEs as tissue-specific enhancers, paving the way for comprehensive understanding of the role of TEs as bona fide enhancers in the cancer genomes.
    DOI:  https://doi.org/10.1038/s41467-023-41081-4
  4. Nat Biotechnol. 2023 Aug 28.
    Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects.
    Emily B Fabyanic, Peng Hu, Qi Qiu, Kiara N Berríos, Daniel R Connolly, Tong Wang, Jennifer Flournoy, Zhaolan Zhou, Rahul M Kohli, Hao Wu.
      Oxidative modification of 5-methylcytosine (5mC) by ten-eleven translocation (TET) DNA dioxygenases generates 5-hydroxymethylcytosine (5hmC), the most abundant form of oxidized 5mC. Existing single-cell bisulfite sequencing methods cannot resolve 5mC and 5hmC, leaving the cell-type-specific regulatory mechanisms of TET and 5hmC largely unknown. Here, we present joint single-nucleus (hydroxy)methylcytosine sequencing (Joint-snhmC-seq), a scalable and quantitative approach that simultaneously profiles 5hmC and true 5mC in single cells by harnessing differential deaminase activity of APOBEC3A toward 5mC and chemically protected 5hmC. Joint-snhmC-seq profiling of single nuclei from mouse brains reveals an unprecedented level of epigenetic heterogeneity of both 5hmC and true 5mC at single-cell resolution. We show that cell-type-specific profiles of 5hmC or true 5mC improve multimodal single-cell data integration, enable accurate identification of neuronal subtypes and uncover context-specific regulatory effects on cell-type-specific genes by TET enzymes.
    DOI:  https://doi.org/10.1038/s41587-023-01909-2
  5. Nucleic Acids Res. 2023 Aug 28. pii: gkad700. [Epub ahead of print]
    HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.
    Viacheslav M Morozov, Alberto Riva, Sadia Sarwar, Wan-Ju Kim, Jianping Li, Lei Zhou, Jonathan D Licht, Yehia Daaka, Alexander M Ishov.
      Incorporation of histone variant H3.3 comprises active territories of chromatin. Exploring the function of H3.3 in prostate cancer (PC), we found that knockout (KO) of H3.3 chaperone HIRA suppresses PC growth in vitro and in xenograft settings, deregulates androgen-induced gene expression and alters androgen receptor (AR) binding within enhancers of target genes. H3.3 affects transcription in multiple ways, including activation of p300 by phosphorylated H3.3 at Ser-31 (H3.3S31Ph), which results in H3K27 acetylation (H3K27Ac) at enhancers. In turn, H3K27Ac recruits bromodomain protein BRD4 for enhancer-promoter interaction and transcription activation. We observed that HIRA KO reduces H3.3 incorporation, diminishes H3.3S31Ph and H3K27Ac, modifies recruitment of BRD4. These results suggest that H3.3-enriched enhancer chromatin serves as a platform for H3K27Ac-mediated BRD4 recruitment, which interacts with and retains AR at enhancers, resulting in transcription reprogramming. In addition, HIRA KO deregulates glucocorticoid- (GR) driven transcription of genes co-regulated by AR and GR, suggesting a common H3.3/HIRA-dependent mechanism of nuclear receptors function. Expression of HIRA complex proteins is increased in PC compared with normal prostate tissue, especially in high-risk PC groups, and is associated with a negative prognosis. Collectively, our results demonstrate function of HIRA-dependent H3.3 pathway in regulation of nuclear receptors activity.
    DOI:  https://doi.org/10.1093/nar/gkad700
  6. Nucleic Acids Res. 2023 Aug 31. pii: gkad718. [Epub ahead of print]
    Optimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements.
    Max Trauernicht, Chaitanya Rastogi, Stefano G Manzo, Harmen J Bussemaker, Bas van Steensel.
      TP53 is a transcription factor that controls multiple cellular processes, including cell cycle arrest, DNA repair and apoptosis. The relation between TP53 binding site architecture and transcriptional output is still not fully understood. Here, we systematically examined in three different cell lines the effects of binding site affinity and copy number on TP53-dependent transcriptional output, and also probed the impact of spacer length and sequence between adjacent binding sites, and of core promoter identity. Paradoxically, we found that high-affinity TP53 binding sites are less potent than medium-affinity sites. TP53 achieves supra-additive transcriptional activation through optimally spaced adjacent binding sites, suggesting a cooperative mechanism. Optimally spaced adjacent binding sites have a ∼10-bp periodicity, suggesting a role for spatial orientation along the DNA double helix. We leveraged these insights to construct a log-linear model that explains activity from sequence features, and to identify new highly active and sensitive TP53 reporters.
    DOI:  https://doi.org/10.1093/nar/gkad718
  7. Nat Methods. 2023 Aug 28.
    scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.
    Wen Li, Jiansen Lu, Ping Lu, Yun Gao, Yichen Bai, Kexuan Chen, Xinjie Su, Mengyao Li, Jun'e Liu, Yijun Chen, Lu Wen, Fuchou Tang.
      The high-order three-dimensional (3D) organization of regulatory genomic elements provides a topological basis for gene regulation, but it remains unclear how multiple regulatory elements across the mammalian genome interact within an individual cell. To address this, herein, we developed scNanoHi-C, which applies Nanopore long-read sequencing to explore genome-wide proximal high-order chromatin contacts within individual cells. We show that scNanoHi-C can reliably and effectively profile 3D chromatin structures and distinguish structure subtypes among individual cells. This method could also be used to detect genomic variations, including copy-number variations and structural variations, as well as to scaffold the de novo assembly of single-cell genomes. Notably, our results suggest that extensive high-order chromatin structures exist in active chromatin regions across the genome, and multiway interactions between enhancers and their target promoters were systematically identified within individual cells. Altogether, scNanoHi-C offers new opportunities to investigate high-order 3D genome structures at the single-cell level.
    DOI:  https://doi.org/10.1038/s41592-023-01978-w
  8. Res Sq. 2023 Aug 16. pii: rs.3.rs-3164817. [Epub ahead of print]
    Competition between transcription and loop extrusion modulates promoter and enhancer dynamics.
    Tom Sexton, Angeliki Platania, Cathie Erb, Mariano Barbieri, Bastien Molcrette, Erwan Grandgirard, Marit de Kort, Karen Meaburn, Tiegh Taylor, Virlana Shchuka, Silvia Kocanova, Guilherme Oliveira, Jennifer Mitchell, Evi Soutoglou, Tineke Lenstra, Nacho Molina, Argyris Papantonis, Kerstin Bystricky.
      The spatiotemporal configuration of genes with distal regulatory elements, and the impact of chromatin mobility on transcription, remain unclear. Loop extrusion is an attractive model for bringing genetic elements together, but how this functionally interacts with transcription is also largely unknown. We combine live tracking of genomic loci and nascent transcripts with molecular dynamics simulations to assess the spatiotemporal arrangement of the Sox2 gene and its enhancer, in response to a battery of perturbations. We find a close link between chromatin mobility and transcriptional status: active elements display more constrained mobility, consistent with confinement within specialized nuclear sites, and alterations in enhancer mobility distinguish poised from transcribing alleles. Strikingly, we find that whereas loop extrusion and transcription factor-mediated clustering contribute to promoter-enhancer proximity, they have antagonistic effects on chromatin dynamics. This provides an experimental framework for the underappreciated role of chromatin dynamics in genome regulation.
    DOI:  https://doi.org/10.21203/rs.3.rs-3164817/v1
  9. J Cell Sci. 2023 Sep 01. pii: jcs.261092. [Epub ahead of print]
    DAXX safeguards heterochromatin formation in embryonic stem cells.
    Antoine Canat, Adeline Veillet, Renaud Batrin, Clara Dubourg, Priscillia Lhoumaud, Pol Arnau-Romero, Maxim V C Greenberg, Frédéric Bonhomme, Paola B Arimondo, Robert Illingworth, Emmanuelle Fabre, Pierre Therizols.
      Genomes comprise a large fraction of repetitive sequences folded into constitutive heterochromatin to protect genome integrity and cell identity. De novo formation of heterochromatin during preimplantation development is an essential step for preserving the ground-state of pluripotency and the self-renewal capacity of embryonic stem cells (ESCs). Yet, the molecular mechanisms responsible for the remodeling of constitutive heterochromatin are largely unknown. Here, we identify that DAXX, an H3.3 chaperone essential for the maintenance of ESCs in the ground state, accumulates in pericentromeric regions independently of DNA methylation. DAXX recruits PML and SETDB1 to promote the formation of heterochromatin, forming foci that are hallmarks of ground-state ESCs. In the absence of DAXX or PML, the 3D-architecture and physical properties of pericentric and peripheral heterochromatin are disrupted, resulting in derepression of major satellite DNA, transposable elements and genes associated with the nuclear lamina. Using epigenome editing tools, we observe that H3.3, and specifically H3.3K9 modification, directly contribute to maintaining pericentromeric chromatin conformation. Altogether, our data reveal that DAXX is crucial for the maintenance and 3D-organization of the heterochromatin compartment and protects ESC viability.
    Keywords:  Chromocenters; DAXX; Embryonic Stem Cell; Heterochromatin; Histone variant H3.3; Nuclear periphery; PML; Pericentromere; SETDB1
    DOI:  https://doi.org/10.1242/jcs.261092
  10. Sci Adv. 2023 Sep;9(35): eadg5234
    Mettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue.
    Alexandra M Maldonado López, Eun Kyung Ko, Sijia Huang, Gina Pacella, Nina Kuprasertkul, Carina A D'souza, Raúl A Reyes Hueros, Hui Shen, Julian Stoute, Heidi Elashal, Morgan Sinkfield, Amy Anderson, Stephen Prouty, Hua-Bing Li, John T Seykora, Kathy Fange Liu, Brian C Capell.
      N6-methyladenosine (m6A) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of m6A in a self-renewing somatic tissue, we deleted Mettl3 in epidermal progenitors in vivo. Mice lacking Mettl3 demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that Mettl3 promotes the m6A-mediated degradation of mRNAs encoding critical histone modifying enzymes. Depletion of Mettl3 results in the loss of m6A on these mRNAs and increases their expression and associated modifications, resulting in widespread gene expression abnormalities that mirror the gross phenotypic abnormalities. Collectively, these results have identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for m6A in the regulation of chromatin modifiers, and underscoring a critical role for Mettl3-catalyzed m6A in proper epithelial development and self-renewal.
    DOI:  https://doi.org/10.1126/sciadv.adg5234
  11. Nucleic Acids Res. 2023 Aug 31. pii: gkad711. [Epub ahead of print]
    The Swi-Snf chromatin remodeling complex mediates gene repression through metabolic control.
    Michael C Church, Andrew Price, Hua Li, Jerry L Workman.
      In eukaryotes, ATP-dependent chromatin remodelers regulate gene expression in response to nutritional and metabolic stimuli. However, altered transcription of metabolic genes may have significant indirect consequences which are currently poorly understood. In this study, we use genetic and molecular approaches to uncover a role for the remodeler Swi-Snf as a critical regulator of metabolism. We find that snfΔ mutants display a cysteine-deficient phenotype, despite growth in nutrient-rich media. This correlates with widespread perturbations in sulfur metabolic gene transcription, including global redistribution of the sulfur-sensing transcription factor Met4. Our findings show how a chromatin remodeler can have a significant impact on a whole metabolic pathway by directly regulating an important gene subset and demonstrate an emerging role for chromatin remodeling complexes as decisive factors in metabolic control.
    DOI:  https://doi.org/10.1093/nar/gkad711
  12. EMBO Rep. 2023 Aug 31. e57032
    Loss of BRD4 induces cell senescence in HSC/HPCs by deregulating histone H3 clipping.
    Hui Yang, Pinpin Sui, Ying Guo, Shi Chen, Marie E Maloof, Guo Ge, Francine Nihozeko, Caroline R Delma, Ganqian Zhu, Peng Zhang, Zhenqing Ye, Edward A Medina, Nagi G Ayad, Ruben Mesa, Stephen D Nimer, Cheng-Ming Chiang, Mingjiang Xu, Yidong Chen, Feng-Chun Yang.
      Bromodomain-containing protein 4 (BRD4) is overexpressed and functionally implicated in various myeloid malignancies. However, the role of BRD4 in normal hematopoiesis remains largely unknown. Here, utilizing an inducible Brd4 knockout mouse model, we find that deletion of Brd4 (Brd4Δ/Δ ) in the hematopoietic system impairs hematopoietic stem cell (HSC) self-renewal and differentiation, which associates with cell cycle arrest and senescence. ATAC-seq analysis shows increased chromatin accessibility in Brd4Δ/Δ hematopoietic stem/progenitor cells (HSC/HPCs). Genome-wide mapping with cleavage under target and release using nuclease (CUT&RUN) assays demonstrate that increased global enrichment of H3K122ac and H3K4me3 in Brd4Δ/Δ HSC/HPCs is associated with the upregulation of senescence-specific genes. Interestingly, Brd4 deletion increases clipped H3 (cH3) which correlates with the upregulation of senescence-specific genes and results in a higher frequency of senescent HSC/HPCs. Re-expression of BRD4 reduces cH3 levels and rescues the senescence rate in Brd4Δ/Δ HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression.
    Keywords:  Brd4; hematopoiesis; histone clipping; senescence
    DOI:  https://doi.org/10.15252/embr.202357032
  13. EMBO J. 2023 Aug 29. e114162
    Changes in adenoviral chromatin organization precede early gene activation upon infection.
    Uwe Schwartz, Tetsuro Komatsu, Claudia Huber, Floriane Lagadec, Conradin Baumgartl, Elisabeth Silberhorn, Margit Nuetzel, Fabienne Rayne, Eugenia Basyuk, Edouard Bertrand, Michael Rehli, Harald Wodrich, Gernot Laengst.
      Within the virion, adenovirus DNA associates with the virus-encoded, protamine-like structural protein pVII. Whether this association is organized, and how genome packaging changes during infection and subsequent transcriptional activation is currently unclear. Here, we combined RNA-seq, MNase-seq, ChIP-seq, and single genome imaging during early adenovirus infection to unveil the structure- and time-resolved dynamics of viral chromatin changes as well as their correlation with gene transcription. Our MNase mapping data indicates that the adenoviral genome is arranged in precisely positioned nucleoprotein particles with nucleosome-like characteristics, that we term adenosomes. We identified 238 adenosomes that are positioned by a DNA sequence code and protect about 60-70 bp of DNA. The incoming adenoviral genome is more accessible at early gene loci that undergo additional chromatin de-condensation upon infection. Histone H3.3 containing nucleosomes specifically replaces pVII at distinct genomic sites and at the transcription start sites of early genes. Acetylation of H3.3 is predominant at the transcription start sites and precedes transcriptional activation. Based on our results, we propose a central role for the viral pVII nucleoprotein architecture, which is required for the dynamic structural changes during early infection, including the regulation of nucleosome assembly prior to transcription initiation. Our study thus may aid the rational development of recombinant adenoviral vectors exhibiting sustained expression in gene therapy.
    Keywords:  adenovirus; chromatin remodeling; early infection; pVII; transcription
    DOI:  https://doi.org/10.15252/embj.2023114162
  14. Cell. 2023 Aug 24. pii: S0092-8674(23)00855-3. [Epub ahead of print]
    Chromatin remodeling of histone H3 variants by DDM1 underlies epigenetic inheritance of DNA methylation.
    Seung Cho Lee, Dexter W Adams, Jonathan J Ipsaro, Jonathan Cahn, Jason Lynn, Hyun-Soo Kim, Benjamin Berube, Viktoria Major, Joseph P Calarco, Chantal LeBlanc, Sonali Bhattacharjee, Umamaheswari Ramu, Daniel Grimanelli, Yannick Jacob, Philipp Voigt, Leemor Joshua-Tor, Robert A Martienssen.
      Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1LSH/HELLS), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1Dnmt1, but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance.
    Keywords:  DNA methylation; DNA replication; chromatin remodeling; epigenetic inheritance; heterochromatin; histone H3.1; histone H3.3; histone MGH3/HTR10; histone modification; transposable elements
    DOI:  https://doi.org/10.1016/j.cell.2023.08.001
  15. Dev Cell. 2023 Aug 23. pii: S1534-5807(23)00399-4. [Epub ahead of print]
    Control of murine brown adipocyte development by GATA6.
    Seoyoung Jun, Anthony R Angueira, Ethan C Fein, Josephine M E Tan, Angela H Weller, Lan Cheng, Kirill Batmanov, Jeff Ishibashi, Alexander P Sakers, Rachel R Stine, Patrick Seale.
      Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia and obesity. BAT derives from the multipotent paraxial mesoderm; however, the identity of embryonic brown fat progenitor cells and regulators of adipogenic commitment are unclear. Here, we performed single-cell gene expression analyses of mesenchymal cells during mouse embryogenesis with a focus on BAT development. We identified cell populations associated with the development of BAT, including Dpp4+ cells that emerge at the onset of adipogenic commitment. Immunostaining and lineage-tracing studies show that Dpp4+ cells constitute the BAT fascia and contribute minorly as adipocyte progenitors. Additionally, we identified the transcription factor GATA6 as a marker of brown adipogenic progenitor cells. Deletion of Gata6 in the brown fat lineage resulted in a striking loss of BAT. Together, these results identify progenitor and transitional cells in the brown adipose lineage and define a crucial role for GATA6 in BAT development.
    Keywords:  DPP4; EBF2; GATA6; UCP1; adipose tissue; brown adipocyte; brown adipocyte development; brown adipogenesis; progenitor
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.003
  16. Nucleic Acids Res. 2023 Aug 31. pii: gkad719. [Epub ahead of print]
    A genetic screen identifies BEND3 as a regulator of bivalent gene expression and global DNA methylation.
    Lounis Yakhou, Anaelle Azogui, Nikhil Gupta, Julien Richard Albert, Fumihito Miura, Laure Ferry, Kosuke Yamaguchi, Sarah Battault, Pierre Therizols, Frédéric Bonhomme, Elouan Bethuel, Arpita Sarkar, Maxim V C Greenberg, Paola B Arimondo, Gael Cristofari, Olivier Kirsh, Takashi Ito, Pierre-Antoine Defossez.
      Epigenetic mechanisms are essential to establish and safeguard cellular identities in mammals. They dynamically regulate the expression of genes, transposable elements and higher-order chromatin structures. Consequently, these chromatin marks are indispensable for mammalian development and alterations often lead to disease, such as cancer. Bivalent promoters are especially important during differentiation and development. Here we used a genetic screen to identify new regulators of a bivalent repressed gene. We identify BEND3 as a regulator of hundreds of bivalent promoters, some of which it represses, and some of which it activates. We show that BEND3 is recruited to a CpG-containg consensus site that is present in multiple copies in many bivalent promoters. Besides having direct effect on the promoters it binds, the loss of BEND3 leads to genome-wide gains of DNA methylation, which are especially marked at regions normally protected by the TET enzymes. DNA hydroxymethylation is reduced in Bend3 mutant cells, possibly as consequence of altered gene expression leading to diminished alpha-ketoglutarate production, thus lowering TET activity. Our results clarify the direct and indirect roles of an important chromatin regulator, BEND3, and, more broadly, they shed light on the regulation of bivalent promoters.
    DOI:  https://doi.org/10.1093/nar/gkad719
  17. Cell Rep. 2023 Aug 31. pii: S2211-1247(23)01090-2. [Epub ahead of print]42(9): 113079
    Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation.
    Marwa M Afifi, Adrijana Crncec, James A Cornwell, Christophe Cataisson, Debasish Paul, Laila M Ghorab, Maria O Hernandez, Madeline Wong, Noemi Kedei, Steven D Cappell.
      Cells can irreversibly exit the cell cycle and become senescent to safeguard against uncontrolled proliferation. While the p53-p21 and p16-Rb pathways are thought to mediate senescence, they also mediate reversible cell cycle arrest (quiescence), raising the question of whether senescence is actually reversible or whether alternative mechanisms underly the irreversibility associated with senescence. Here, we show that senescence is irreversible and that commitment to and maintenance of senescence are mediated by irreversible MYC degradation. Senescent cells start dividing when a non-degradable MYC mutant is expressed, and quiescent cells convert to senescence when MYC is knocked down. In early oral carcinogenesis, epithelial cells exhibit MYC loss and become senescent as a safeguard against malignant transformation. Later stages of oral premalignant lesions exhibit elevated MYC levels and cellular dysplasia. Thus, irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation, but bypassing this degradation may allow tumor cells to escape during cancer initiation.
    Keywords:  CDK4/6; CP: Cell biology; MEK; MYC; cell cycle; palbociclib; pre-malignant lesions; senescence; time-lapse imaging; trametinib
    DOI:  https://doi.org/10.1016/j.celrep.2023.113079
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