bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–01–15
twenty-two papers selected by
Connor Rogerson, University of Cambridge
  1. Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4.
  2. ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs.
  3. ZBTB18 restricts chromatin accessibility and prevents transcriptional adaptations that drive metastasis.
  4. DNA dioxygenases Tet2/3 regulate gene promoter accessibility and chromatin topology in lineage-specific loci to control epithelial differentiation.
  5. xcore: an R package for inference of gene expression regulators.
  6. A transcription factor atlas of directed differentiation.
  7. Chd5 regulates the transcription factor Six3 to promote neuronal differentiation.
  8. PRR14 organizes H3K9me3-modified heterochromatin at the nuclear lamina.
  9. Enhancer architecture and chromatin accessibility constrain phenotypic space during Drosophila development.
  10. Human SMARCA5 is continuously required to maintain nucleosome spacing.
  11. KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer.
  12. NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells.
  13. General transcription factor TAF4 antagonizes epigenetic silencing by Polycomb to maintain intestine stem cell functions.
  14. Changes in PRC1 activity during interphase modulate lineage transition in pluripotent cells.
  15. Activating and repressing gene expression between chromosomes during stochastic fate specification.
  16. The homeodomain of Oct4 is a dimeric binder of methylated CpG elements.
  17. Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes.
  18. Dynamic chromatin regulatory programs during embryogenesis of hexaploid wheat.
  19. MDC1 maintains active elongation complexes of RNA polymerase II.
  20. A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer.
  21. TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma.
  22. Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation.
  1. Nucleic Acids Res. 2023 Jan 05. pii: gkac1230. [Epub ahead of print]
    Antagonistic action of GPS2 and KDM1A at enhancers governs alternative macrophage activation by interleukin 4.
    Zhiqiang Huang, Astradeni Efthymiadou, Ning Liang, Rongrong Fan, Eckardt Treuter.
      The Th2 cytokine interleukin 4 (IL4) promotes macrophage differentiation into alternative subtypes and plays important roles in physiology, in metabolic and inflammatory diseases, in cancer and in tissue regeneration. While the regulatory transcription factor networks governing IL4 signaling are already well-characterized, it is currently less understood which transcriptional coregulators are involved and how they operate mechanistically. In this study, we discover that G protein pathway suppressor 2 (GPS2), a core subunit of the HDAC3 corepressor complex assembled by SMRT and NCOR, represses IL4-dependent enhancer activation in mouse macrophages. Our genome-wide and gene-specific characterization revealed that, instead of directly repressing STAT6, chromatin-bound GPS2 cooperates with SMRT and NCOR to antagonize enhancer activation by lysine demethylase 1A (KDM1A, LSD1). Mechanistically, corepressor depletion increased KDM1A recruitment to enhancers linked to IL4-induced genes, accompanied by demethylation of the repressive histone marks H3K9me2/3 without affecting H3K4me1/2, the classic KDM1A substrates for demethylation in other cellular contexts. This in turn caused enhancer and gene activation already in the absence of IL4/STAT6 and sensitized the STAT6-dependent IL4 responsiveness of macrophages. Thus, our work identified with the antagonistic action of a GPS2-containing corepressor complex and the lysine demethylase KDM1A a hitherto unknown epigenetic corepressor-coactivator switching mechanism that governs alternative macrophage activation.
    DOI:  https://doi.org/10.1093/nar/gkac1230
  2. Nat Commun. 2023 Jan 13. 14(1): 213
    ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs.
    Haoxi Chai, Harianto Tjong, Peng Li, Wei Liao, Ping Wang, Chee Hong Wong, Chew Yee Ngan, Warren J Leonard, Chia-Lin Wei, Yijun Ruan.
      Connecting genes to their cis-regulatory elements has been enabled by genome-wide mapping of chromatin interactions using proximity ligation in ChIA-PET, Hi-C, and their derivatives. However, these methods require millions of input cells for high-quality data and thus are unsuitable for many studies when only limited cells are available. Conversely, epigenomic profiling via transposase digestion in ATAC-seq requires only hundreds to thousands of cells to robustly map open chromatin associated with transcription activity, but it cannot directly connect active genes to their distal enhancers. Here, we combine proximity ligation in ChIA-PET and transposase accessibility in ATAC-seq into ChIATAC to efficiently map interactions between open chromatin loci in low numbers of input cells. We validate ChIATAC in Drosophila cells and optimize it for mapping 3D epigenomes in human cells robustly. Applying ChIATAC to primary human T cells, we reveal mechanisms that topologically regulate transcriptional programs during T cell activation.
    DOI:  https://doi.org/10.1038/s41467-023-35879-5
  3. Sci Adv. 2023 Jan 06. 9(1): eabq3951
    ZBTB18 restricts chromatin accessibility and prevents transcriptional adaptations that drive metastasis.
    Ruishan Wang, Akshita B Bhatt, Benjamin A Minden-Birkenmaier, Olivia K Travis, Srishti Tiwari, Hong Jia, Wojciech Rosikiewicz, Ophelie Martinot, Eleanor Childs, Robin Loesch, Guenole Tossou, Sophie Jamieson, David Finkelstein, Beisi Xu, Myriam Labelle.
      Metastases arise from rare cancer cells that successfully adapt to the diverse microenvironments encountered during dissemination through the bloodstream and colonization of distant tissues. How cancer cells acquire the ability to appropriately respond to microenvironmental stimuli remains largely unexplored. Here, we report an epigenetic pliancy mechanism that allows cancer cells to successfully metastasize. We find that a decline in the activity of the transcriptional repressor ZBTB18 defines metastasis-competent cancer cells in mouse models. Restoration of ZBTB18 activity reduces chromatin accessibility at the promoters of genes that drive metastasis, such as Tgfbr2, and this prevents TGFβ1 pathway activation and consequently reduces cell migration and invasion. Besides repressing the expression of metastatic genes, ZBTB18 also induces widespread chromatin closing, a global epigenetic adaptation previously linked to reduced phenotypic flexibility. Thus, ZBTB18 is a potent chromatin regulator, and the loss of its activity enhances chromatin accessibility and transcriptional adaptations that promote the phenotypic changes required for metastasis.
    DOI:  https://doi.org/10.1126/sciadv.abq3951
  4. Sci Adv. 2023 Jan 13. 9(2): eabo7605
    DNA dioxygenases Tet2/3 regulate gene promoter accessibility and chromatin topology in lineage-specific loci to control epithelial differentiation.
    Guo-Dong Chen, Iqra Fatima, Qin Xu, Elena Rozhkova, Michael Y Fessing, Andrei N Mardaryev, Andrey A Sharov, Guo-Liang Xu, Vladimir A Botchkarev.
      Execution of lineage-specific differentiation programs requires tight coordination between many regulators including Ten-eleven translocation (TET) family enzymes, catalyzing 5-methylcytosine oxidation in DNA. Here, by using Keratin 14-Cre-driven ablation of Tet genes in skin epithelial cells, we demonstrate that ablation of Tet2/Tet3 results in marked alterations of hair shape and length followed by hair loss. We show that, through DNA demethylation, Tet2/Tet3 control chromatin accessibility and Dlx3 binding and promoter activity of the Krt25 and Krt28 genes regulating hair shape, as well as regulate interactions between the Krt28 gene promoter and distal enhancer. Moreover, Tet2/Tet3 also control three-dimensional chromatin topology in Keratin type I/II gene loci via DNA methylation-independent mechanisms. These data demonstrate the essential roles for Tet2/3 in establishment of lineage-specific gene expression program and control of Dlx3/Krt25/Krt28 axis in hair follicle epithelial cells and implicate modulation of DNA methylation as a novel approach for hair growth control.
    DOI:  https://doi.org/10.1126/sciadv.abo7605
  5. BMC Bioinformatics. 2023 Jan 11. 24(1): 14
    xcore: an R package for inference of gene expression regulators.
    Maciej Migdał, Takahiro Arakawa, Satoshi Takizawa, Masaaki Furuno, Harukazu Suzuki, Erik Arner, Cecilia Lanny Winata, Bogumił Kaczkowski.
       BACKGROUND: Elucidating the Transcription Factors (TFs) that drive the gene expression changes in a given experiment is a common question asked by researchers. The existing methods rely on the predicted Transcription Factor Binding Site (TFBS) to model the changes in the motif activity. Such methods only work for TFs that have a motif and assume the TF binding profile is the same in all cell types.
    RESULTS: Given the wealth of the ChIP-seq data available for a wide range of the TFs in various cell types, we propose that gene expression modeling can be done using ChIP-seq "signatures" directly, effectively skipping the motif finding and TFBS prediction steps. We present xcore, an R package that allows TF activity modeling based on ChIP-seq signatures and the user's gene expression data. We also provide xcoredata a companion data package that provides a collection of preprocessed ChIP-seq signatures. We demonstrate that xcore leads to biologically relevant predictions using transforming growth factor beta induced epithelial-mesenchymal transition time-courses, rinderpest infection time-courses, and embryonic stem cells differentiated to cardiomyocytes time-course profiled with Cap Analysis Gene Expression.
    CONCLUSIONS: xcore provides a simple analytical framework for gene expression modeling using linear models that can be easily incorporated into differential expression analysis pipelines. Taking advantage of public ChIP-seq databases, xcore can identify meaningful molecular signatures and relevant ChIP-seq experiments.
    Keywords:  ChIP-seq; Gene expression; Gene regulation; Regression; Transcription factors
    DOI:  https://doi.org/10.1186/s12859-022-05084-0
  6. Cell. 2023 Jan 05. pii: S0092-8674(22)01470-2. [Epub ahead of print]186(1): 209-229.e26
    A transcription factor atlas of directed differentiation.
    Julia Joung, Sai Ma, Tristan Tay, Kathryn R Geiger-Schuller, Paul C Kirchgatterer, Vanessa K Verdine, Baolin Guo, Mario A Arias-Garcia, William E Allen, Ankita Singh, Olena Kuksenko, Omar O Abudayyeh, Jonathan S Gootenberg, Zhanyan Fu, Rhiannon K Macrae, Jason D Buenrostro, Aviv Regev, Feng Zhang.
      Transcription factors (TFs) regulate gene programs, thereby controlling diverse cellular processes and cell states. To comprehensively understand TFs and the programs they control, we created a barcoded library of all annotated human TF splice isoforms (>3,500) and applied it to build a TF Atlas charting expression profiles of human embryonic stem cells (hESCs) overexpressing each TF at single-cell resolution. We mapped TF-induced expression profiles to reference cell types and validated candidate TFs for generation of diverse cell types, spanning all three germ layers and trophoblasts. Targeted screens with subsets of the library allowed us to create a tailored cellular disease model and integrate mRNA expression and chromatin accessibility data to identify downstream regulators. Finally, we characterized the effects of combinatorial TF overexpression by developing and validating a strategy for predicting combinations of TFs that produce target expression profiles matching reference cell types to accelerate cellular engineering efforts.
    Keywords:  ORF overexpression; cell engineering; cellular disease modeling; combinatorial perturbation; gene regulation; genetic screening; neural progenitor; pluripotent stem cell; single cell profiling; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2022.11.026
  7. Stem Cells. 2023 Jan 13. pii: sxad002. [Epub ahead of print]
    Chd5 regulates the transcription factor Six3 to promote neuronal differentiation.
    Padmina Shrestha, Anbalagan Jaganathan, Dhananjay Huilgol, Carlos Ballon, Yon Hwangbo, Alea A Mills.
      Chromodomain helicase DNA-binding protein 5 (Chd5) is an ATP-dependent chromatin remodeler that promotes neuronal differentiation. However, the mechanism behind the action of Chd5 during neurogenesis is not clearly understood. Here we use transcriptional profiling of cells obtained from Chd5 deficient mice at early and late stages of neuronal differentiation to show that Chd5 regulates neurogenesis by directing stepwise transcriptional changes. During early stages of neurogenesis, Chd5 promotes expression of the proneural transcription factor Six3 to repress Wnt5a, a non-canonical Wnt ligand essential for the maturation of neurons. This previously unappreciated ability of Chd5 to transcriptionally repress neuronal maturation factors is critical for both lineage specification and maturation. Thus, Chd5 facilitates early transcriptional changes in neural stem cells, thereby initiating transcriptional programs essential for neuronal fate specification.
    Keywords:  Neural stem cells; chromatin; differentiation; maturation; transcription
    DOI:  https://doi.org/10.1093/stmcls/sxad002
  8. Nucleus. 2023 Dec;14(1): 2165602
    PRR14 organizes H3K9me3-modified heterochromatin at the nuclear lamina.
    Anna A Kiseleva, Yu-Chia Cheng, Cheryl L Smith, Richard A Katz, Andrey Poleshko.
      The eukaryotic genome is organized in three dimensions within the nucleus. Transcriptionally active chromatin is spatially separated from silent heterochromatin, a large fraction of which is located at the nuclear periphery. However, the mechanisms by which chromatin is localized at the nuclear periphery remain poorly understood. Here we demonstrate that Proline Rich 14 (PRR14) protein organizes H3K9me3-modified heterochromatin at the nuclear lamina. We show that PRR14 dynamically associates with both the nuclear lamina and heterochromatin, and is able to reorganize heterochromatin in the nucleus of interphase cells independent of mitosis. We characterize two functional HP1-binding sites within PRR14 that contribute to its association with heterochromatin. We also demonstrate that PPR14 forms an anchoring surface for heterochromatin at the nuclear lamina where it interacts dynamically with HP1-associated chromatin. Our study proposes a model of dynamic heterochromatin organization at the nuclear lamina via the PRR14 tethering protein.
    Keywords:  FRAP; H3K9me3; HP1; PRR14; heterochromatin; nuclear lamina
    DOI:  https://doi.org/10.1080/19491034.2023.2165602
  9. Dev Cell. 2023 Jan 09. pii: S1534-5807(22)00847-4. [Epub ahead of print]58(1): 51-62.e4
    Enhancer architecture and chromatin accessibility constrain phenotypic space during Drosophila development.
    Rafael Galupa, Gilberto Alvarez-Canales, Noa Ottilie Borst, Timothy Fuqua, Lautaro Gandara, Natalia Misunou, Kerstin Richter, Mariana R P Alves, Esther Karumbi, Melinda Liu Perkins, Tin Kocijan, Christine A Rushlow, Justin Crocker.
      Developmental enhancers bind transcription factors and dictate patterns of gene expression during development. Their molecular evolution can underlie phenotypical evolution, but the contributions of the evolutionary pathways involved remain little understood. Here, using mutation libraries in Drosophila melanogaster embryos, we observed that most point mutations in developmental enhancers led to changes in gene expression levels but rarely resulted in novel expression outside of the native pattern. In contrast, random sequences, often acting as developmental enhancers, drove expression across a range of cell types; random sequences including motifs for transcription factors with pioneer activity acted as enhancers even more frequently. Our findings suggest that the phenotypic landscapes of developmental enhancers are constrained by enhancer architecture and chromatin accessibility. We propose that the evolution of existing enhancers is limited in its capacity to generate novel phenotypes, whereas the activity of de novo elements is a primary source of phenotypic novelty.
    Keywords:  Drosophila melanogaster; development; enhancers; evolution; gene regulation; novel expression patterns; phenotypical novelties; pioneer factors; random sequences; reporter assays
    DOI:  https://doi.org/10.1016/j.devcel.2022.12.003
  10. Mol Cell. 2023 Jan 06. pii: S1097-2765(22)01175-3. [Epub ahead of print]
    Human SMARCA5 is continuously required to maintain nucleosome spacing.
    Monica L Bomber, Jing Wang, Qi Liu, Kelly R Barnett, Hillary M Layden, Emily Hodges, Kristy R Stengel, Scott W Hiebert.
      Genetic models suggested that SMARCA5 was required for DNA-templated events including transcription, DNA replication, and DNA repair. We engineered a degron tag into the endogenous alleles of SMARCA5, a catalytic component of the imitation switch complexes in three different human cell lines to define the effects of rapid degradation of this key regulator. Degradation of SMARCA5 was associated with a rapid increase in global nucleosome repeat length, which may allow greater chromatin compaction. However, there were few changes in nascent transcription within the first 6 h of degradation. Nevertheless, we demonstrated a requirement for SMARCA5 to control nucleosome repeat length at G1/S and during the S phase. SMARCA5 co-localized with CTCF and H2A.Z, and we found a rapid loss of CTCF DNA binding and disruption of nucleosomal phasing around CTCF binding sites. This spatiotemporal analysis indicates that SMARCA5 is continuously required for maintaining nucleosomal spacing.
    Keywords:  ATAC-seq; CTCF; H2A.Z; MNase-seq; PRO-seq; SMARCA5; chromatin; nucleosome repeat length
    DOI:  https://doi.org/10.1016/j.molcel.2022.12.018
  11. Cancer Res. 2023 Jan 13. pii: CAN-22-1444. [Epub ahead of print]
    KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer.
    Hong Qiu, Vladimir Makarov, Jennifer K Bolzenius, Angela Halstead, Yvonne Parker, Allen Wang, Gopakumar V Iyer, Hannah Wise, Daniel Kim, Varna Thayaparan, Daniel J Lindner, Georges-Pascal Haber, Angela H Ting, Bing Ren, Timothy A Chan, Vivek Arora, David B Solit, Byron H Lee.
      Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations impact the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1444
  12. Development. 2023 Jan 09. pii: dev.201155. [Epub ahead of print]
    NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells.
    Katsiaryna Maskalenka, Gökberk Alagöz, Felix Krueger, Joshua Wright, Maria Rostovskaya, Asif Nakhuda, Adam Bendall, Christel Krueger, Simon Walker, Aylwyn Scally, Peter J Rugg-Gunn.
      Gene duplication events can drive evolution by providing genetic material for new gene functions, and create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naïve-state pluripotent stem cells. Sequence analysis and epitope-tagging revealed that NANOGP1 is protein-coding with an intact homeobox domain. The duplication that created NANOGP1 occurred earlier in primate evolution than previously thought and has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways including homeodomain point mutations. NANOGP1 is a strong inducer of naïve pluripotency; however, unlike NANOG, it is not required to maintain the undifferentiated status of human naïve pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development.
    Keywords:  Evolution; Gene duplication; Pluripotency; Pseudogene; Reprogramming; Transcription factor
    DOI:  https://doi.org/10.1242/dev.201155
  13. Cell Death Differ. 2023 Jan 13.
    General transcription factor TAF4 antagonizes epigenetic silencing by Polycomb to maintain intestine stem cell functions.
    Susanna Säisä-Borreill, Guillaume Davidson, Thomas Kleiber, Andréa Thevenot, Elisabeth Martin, Stanislas Mondot, Hervé Blottière, Alexandra Helleux, Gabrielle Mengus, Michelina Plateroti, Isabelle Duluc, Irwin Davidson, Jean-Noel Freund.
      Taf4 (TATA-box binding protein-associated factor 4) is a subunit of the general transcription factor TFIID, a component of the RNA polymerase II pre-initiation complex that interacts with tissue-specific transcription factors to regulate gene expression. Properly regulated gene expression is particularly important in the intestinal epithelium that is constantly renewed from stem cells. Tissue-specific inactivation of Taf4 in murine intestinal epithelium during embryogenesis compromised gut morphogenesis and the emergence of adult-type stem cells. In adults, Taf4 loss impacted the stem cell compartment and associated Paneth cells in the stem cell niche, epithelial turnover and differentiation of mature cells, thus exacerbating the response to inflammatory challenge. Taf4 inactivation ex vivo in enteroids prevented budding formation and maintenance and caused broad chromatin remodeling and a strong reduction in the numbers of stem and progenitor cells with a concomitant increase in an undifferentiated cell population that displayed high activity of the Ezh2 and Suz12 components of Polycomb Repressive Complex 2 (PRC2). Treatment of Taf4-mutant enteroids with a specific Ezh2 inhibitor restored buddings, cell proliferation and the stem/progenitor compartment. Taf4 loss also led to increased PRC2 activity in cells of adult crypts associated with modification of the immune/inflammatory microenvironment that potentiated Apc-driven tumorigenesis. Our results reveal a novel function of Taf4 in antagonizing PRC2-mediated repression of the stem cell gene expression program to assure normal development, homeostasis, and immune-microenvironment of the intestinal epithelium.
    DOI:  https://doi.org/10.1038/s41418-022-01109-6
  14. Nat Commun. 2023 Jan 12. 14(1): 180
    Changes in PRC1 activity during interphase modulate lineage transition in pluripotent cells.
    Helena G Asenjo, María Alcazar-Fabra, Mencía Espinosa-Martínez, Lourdes Lopez-Onieva, Amador Gallardo, Emilia Dimitrova, Angelika Feldmann, Tomas Pachano, Jordi Martorell-Marugán, Pedro Carmona-Sáez, Antonio Sanchez-Pozo, Álvaro Rada-Iglesias, Robert J Klose, David Landeira.
      The potential of pluripotent cells to respond to developmental cues and trigger cell differentiation is enhanced during the G1 phase of the cell cycle, but the molecular mechanisms involved are poorly understood. Variations in polycomb activity during interphase progression have been hypothesized to regulate the cell-cycle-phase-dependent transcriptional activation of differentiation genes during lineage transition in pluripotent cells. Here, we show that recruitment of Polycomb Repressive Complex 1 (PRC1) and associated molecular functions, ubiquitination of H2AK119 and three-dimensional chromatin interactions, are enhanced during S and G2 phases compared to the G1 phase. In agreement with the accumulation of PRC1 at target promoters upon G1 phase exit, cells in S and G2 phases show firmer transcriptional repression of developmental regulator genes that is drastically perturbed upon genetic ablation of the PRC1 catalytic subunit RING1B. Importantly, depletion of RING1B during retinoic acid stimulation interferes with the preference of mouse embryonic stem cells (mESCs) to induce the transcriptional activation of differentiation genes in G1 phase. We propose that incremental enrolment of polycomb repressive activity during interphase progression reduces the tendency of cells to respond to developmental cues during S and G2 phases, facilitating activation of cell differentiation in the G1 phase of the pluripotent cell cycle.
    DOI:  https://doi.org/10.1038/s41467-023-35859-9
  15. Cell Rep. 2022 Dec 29. pii: S2211-1247(22)01809-5. [Epub ahead of print]42(1): 111910
    Activating and repressing gene expression between chromosomes during stochastic fate specification.
    Elizabeth A Urban, Chaim Chernoff, Kayla Viets Layng, Jeong Han, Caitlin Anderson, Daniel Konzman, Robert J Johnston.
      DNA elements act across long genomic distances to regulate gene expression. During transvection in Drosophila, DNA elements on one allele of a gene act between chromosomes to regulate expression of the other allele. Little is known about the biological roles and developmental regulation of transvection. Here, we study the stochastic expression of spineless (ss) in photoreceptors in the fly eye to understand transvection. We determine a biological role for transvection in regulating expression of naturally occurring ss alleles. We identify DNA elements required for activating and repressing transvection. Different enhancers participate in transvection at different times during development to promote gene expression and specify cell fates. Bringing a silencer element on a heterologous chromosome into proximity with the ss locus "reconstitutes" the gene, leading to repression. Our studies show that transvection regulates gene expression via distinct DNA elements at specific timepoints in development, with implications for genome organization and architecture.
    Keywords:  CP: Molecular biology; Drosophila; R7; enhancer; fly; pairing; retina; silencer; spineless; stochastic; transvection
    DOI:  https://doi.org/10.1016/j.celrep.2022.111910
  16. Nucleic Acids Res. 2023 Jan 12. pii: gkac1262. [Epub ahead of print]
    The homeodomain of Oct4 is a dimeric binder of methylated CpG elements.
    Daisylyn Senna Tan, Shun Lai Cheung, Ya Gao, Maike Weinbuch, Haoqing Hu, Liyang Shi, Shih-Chieh Ti, Andrew P Hutchins, Vlad Cojocaru, Ralf Jauch.
      Oct4 is essential to maintain pluripotency and has a pivotal role in establishing the germline. Its DNA-binding POU domain was recently found to bind motifs with methylated CpG elements normally associated with epigenetic silencing. However, the mode of binding and the consequences of this capability has remained unclear. Here, we show that Oct4 binds to a compact palindromic DNA element with a methylated CpG core (CpGpal) in alternative states of pluripotency and during cellular reprogramming towards induced pluripotent stem cells (iPSCs). During cellular reprogramming, typical Oct4 bound enhancers are uniformly demethylated, with the prominent exception of the CpGpal sites where DNA methylation is often maintained. We demonstrate that Oct4 cooperatively binds the CpGpal element as a homodimer, which contrasts with the ectoderm-expressed POU factor Brn2. Indeed, binding to CpGpal is Oct4-specific as other POU factors expressed in somatic cells avoid this element. Binding assays combined with structural analyses and molecular dynamic simulations show that dimeric Oct4-binding to CpGpal is driven by the POU-homeodomain whilst the POU-specific domain is detached from DNA. Collectively, we report that Oct4 exerts parts of its regulatory function in the context of methylated DNA through a DNA recognition mechanism that solely relies on its homeodomain.
    DOI:  https://doi.org/10.1093/nar/gkac1262
  17. Nat Cell Biol. 2023 Jan 12.
    Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes.
    Christina E Sparbier, Andrea Gillespie, Juliana Gomez, Nishi Kumari, Ali Motazedian, Kah Lok Chan, Charles C Bell, Omer Gilan, Yih-Chih Chan, Sarah Popp, Daniel J Gough, Melanie A Eckersley-Maslin, Sarah-Jane Dawson, Paul J Lehner, Kate D Sutherland, Patricia Ernst, Gerard M McGeehan, Enid Y N Lam, Marian L Burr, Mark A Dawson.
      Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole-genome CRISPR-Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin-KMT2A/B complexes in maintaining bivalency. Genetic loss or pharmacological inhibition of Menin unexpectedly phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. While Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals therapeutic opportunities that can be leveraged through inhibition of Menin.
    DOI:  https://doi.org/10.1038/s41556-022-01056-x
  18. Genome Biol. 2023 Jan 13. 24(1): 7
    Dynamic chromatin regulatory programs during embryogenesis of hexaploid wheat.
    Long Zhao, Yiman Yang, Jinchao Chen, Xuelei Lin, Hao Zhang, Hao Wang, Hongzhe Wang, Xiaomin Bie, Jiafu Jiang, Xiaoqi Feng, Xiangdong Fu, Xiansheng Zhang, Zhuo Du, Jun Xiao.
       BACKGROUND: Plant and animal embryogenesis have conserved and distinct features. Cell fate transitions occur during embryogenesis in both plants and animals. The epigenomic processes regulating plant embryogenesis remain largely elusive.
    RESULTS: Here, we elucidate chromatin and transcriptomic dynamics during embryogenesis of the most cultivated crop, hexaploid wheat. Time-series analysis reveals stage-specific and proximal-distal distinct chromatin accessibility and dynamics concordant with transcriptome changes. Following fertilization, the remodeling kinetics of H3K4me3, H3K27ac, and H3K27me3 differ from that in mammals, highlighting considerable species-specific epigenomic dynamics during zygotic genome activation. Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 deposition is important for embryo establishment. Later H3K27ac, H3K27me3, and chromatin accessibility undergo dramatic remodeling to establish a permissive chromatin environment facilitating the access of transcription factors to cis-elements for fate patterning. Embryonic maturation is characterized by increasing H3K27me3 and decreasing chromatin accessibility, which likely participates in restricting totipotency while preventing extensive organogenesis. Finally, epigenomic signatures are correlated with biased expression among homeolog triads and divergent expression after polyploidization, revealing an epigenomic contributor to subgenome diversification in an allohexaploid genome.
    CONCLUSIONS: Collectively, we present an invaluable resource for comparative and mechanistic analysis of the epigenomic regulation of crop embryogenesis.
    DOI:  https://doi.org/10.1186/s13059-022-02844-2
  19. Cell Rep. 2023 Jan 12. pii: S2211-1247(22)01883-6. [Epub ahead of print]42(1): 111979
    MDC1 maintains active elongation complexes of RNA polymerase II.
    George Pappas, Sebastian Howen Nesgaard Munk, Kenji Watanabe, Quentin Thomas, Zita Gál, Helena Hagner Gram, MyungHee Lee, Daniel Gómez-Cabello, Dimitris Christos Kanellis, Pedro Olivares-Chauvet, Dorthe Helena Larsen, Lea Haarup Gregersen, Apolinar Maya-Mendoza, Panagiotis Galanos, Jiri Bartek.
      The role of MDC1 in the DNA damage response has been extensively studied; however, its impact on other cellular processes is not well understood. Here, we describe the role of MDC1 in transcription as a regulator of RNA polymerase II (RNAPII). Depletion of MDC1 causes a genome-wide reduction in the abundance of actively engaged RNAPII elongation complexes throughout the gene body of protein-encoding genes under unperturbed conditions. Decreased engaged RNAPII subsequently alters the assembly of the spliceosome complex on chromatin, leading to changes in pre-mRNA splicing. Mechanistically, the S/TQ domain of MDC1 modulates RNAPII-mediated transcription. Upon genotoxic stress, MDC1 promotes the abundance of engaged RNAPII complexes at DNA breaks, thereby stimulating nascent transcription at the damaged sites. Of clinical relevance, cancer cells lacking MDC1 display hypersensitivity to RNAPII inhibitors. Overall, we unveil a role of MDC1 in RNAPII-mediated transcription with potential implications for cancer treatment.
    Keywords:  CP: Molecular biology; DNA double-strand breaks; MDC1; RNA polymerase II; cancer; pre-mRNA splicing; transcription elongation
    DOI:  https://doi.org/10.1016/j.celrep.2022.111979
  20. Cell Death Dis. 2023 Jan 06. 14(1): 8
    A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer.
    Yongheng Chen, Ying Ying, Maolin Wang, Canjie Ma, Min Jia, Liang Shi, Shilan Wang, Xiangyi Zheng, Wei Chen, Xing-Sheng Shu.
      Abnormal activities of distal cis-regulatory elements (CREs) contribute to the initiation and progression of cancer. Gain of super-enhancer (SE), a highly active distal CRE, is essential for the activation of key oncogenes in various cancers. However, the mechanism of action for most tumor-specific SEs still largely remains elusive. Here, we report that a candidate oncogene ETS2 was activated by a distal SE in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The SE physically interacted with the ETS2 promoter and was required for the transcription activation of ETS2. Strikingly, the ETS2-SE activity was dramatically upregulated in both IBD and CRC tissues when compared to normal colon controls and was strongly correlated with the level of ETS2 expression. The tumor-specific activation of ETS2-SE was further validated by increased enhancer RNA transcription from this region in CRC. Intriguingly, a known IBD-risk SNP resides in the ETS2-SE and the genetic variant modulated the level of ETS2 expression through affecting the binding of an oncogenic transcription factor MECOM. Silencing of MECOM induced significant downregulation of ETS2 in CRC cells, and the level of MECOM and ETS2 correlated well with each other in CRC and IBD samples. Functionally, MECOM and ETS2 were both required for maintaining the colony-formation and sphere-formation capacities of CRC cells and MECOM was crucial for promoting migration. Taken together, we uncovered a novel disease-specific SE that distantly drives oncogenic ETS2 expression in IBD and CRC and delineated a mechanistic link between non-coding genetic variation and epigenetic regulation of gene transcription.
    DOI:  https://doi.org/10.1038/s41419-022-05513-1
  21. Sci Adv. 2023 Jan 06. 9(1): eadd0960
    TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma.
    Ya-Qin Wang, Dong-Hong Wu, Denghui Wei, Jia-Yi Shen, Zi-Wei Huang, Xiao-Yu Liang, William C S Cho, Jun Ma, Jiawei Lv, Yu-Pei Chen.
      The molecular basis underlying nasopharyngeal carcinoma (NPC) remains unclear. Recent progress in transcriptional regulatory network analysis helps identify the master regulator (MR) proteins that transcriptionally define malignant tumor phenotypes. Here, we investigated transcription factor-target interactions and identified TEA domain transcription factor 4 (TEAD4) as an MR of high-risk NPC. Precisely, TEAD4 promoted NPC migration, invasion and cisplatin resistance, depending on its autopalmitoylation. Mechanistically, YTHDF2 (YTH domain family 2) recognized WTAP (Wilms tumor 1-associating protein)-mediated TEAD4 m6A methylation to facilitate its stability and led to aberrant up-regulation of TEAD4. Up-regulated TEAD4 further drove NPC progression by transcriptionally activating BZW2 (basic leucine zipper and W2 domains 2) to induce the oncogenic AKT pathway. Moreover, the transcriptional activity of TEAD4 was independent of its canonical coactivators YAP/TAZ. Clinically, TEAD4 serves as an independent predictor of unfavorable prognosis and cisplatin response in NPC. Our data revealed the crucial role of TEAD4 in driving tumor malignancy, thus, may provide therapeutic vulnerability in NPC.
    DOI:  https://doi.org/10.1126/sciadv.add0960
  22. Cell Rep. 2023 Jan 04. pii: S2211-1247(22)01843-5. [Epub ahead of print]42(1): 111942
    Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation.
    Jialin Sun, Sivan Osenberg, Austin Irwin, Li-Hua Ma, Nigel Lee, Yangfei Xiang, Feng Li, Ying-Wooi Wan, In-Hyun Park, Mirjana Maletic-Savatic, Nurit Ballas.
      Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced astrocyte gene expression. Notably, however, astrocytes are unable to develop complex mature morphology due to cell- and non-cell-autonomous aberrations caused by MECP2 mutations. Thus, MECP2 mutations critically impact key cellular and molecular features of human astrocytes and, hence, their ability to interact and support the structural and functional maturation of neurons.
    Keywords:  CP: Neuroscience; MeCP2; Rett syndrome; energy metabolism; human astrocytes; human neurons; mitochondria; morphology; neurodevelopment; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2022.111942
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