bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2020–08–16
twenty-two papers selected by
Connor Rogerson, University of Cambridge, MRC Cancer Unit
  1. Ybx1 fine-tunes PRC2 activities to control embryonic brain development.
  2. Integrative analyses of single-cell transcriptome and regulome using MAESTRO.
  3. Physical modeling of the heritability and maintenance of epigenetic modifications.
  4. Deacetylation of H4 lysine16 affects acetylation of lysine residues in histone H3 and H4 and promotes transcription of constitutive genes.
  5. N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2.
  6. Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells.
  7. Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential.
  8. YTHDF1 promotes gastric carcinogenesis by controlling translation of FZD7.
  9. Nucleosome allostery in pioneer transcription factor binding.
  10. Differential Histone Distribution Patterns in Induced Asymmetrically Dividing Mouse Embryonic Stem Cells.
  11. Runx2+ Niche Cells Maintain Incisor Mesenchymal Tissue Homeostasis through IGF Signaling.
  12. NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level.
  13. The epigenomics of sarcoma.
  14. Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis.
  15. Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.
  16. Functional definition of a transcription factor hierarchy regulating T cell lineage commitment.
  17. SurvivalMeth: a web server to investigate the effect of DNA methylation-related functional elements on prognosis.
  18. BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage.
  19. Advances in Chromatin and Chromosome Research: Perspectives from Multiple Fields.
  20. Enhancing the interpretability of transcription factor binding site prediction using attention mechanism.
  21. Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors.
  22. The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors.
  1. Nat Commun. 2020 Aug 13. 11(1): 4060
    Ybx1 fine-tunes PRC2 activities to control embryonic brain development.
    Myron K Evans, Yurika Matsui, Beisi Xu, Catherine Willis, Jennifer Loome, Luis Milburn, Yiping Fan, Vishwajeeth Pagala, Jamy C Peng.
      Chromatin modifiers affect spatiotemporal gene expression programs that underlie organismal development. The Polycomb repressive complex 2 (PRC2) is a crucial chromatin modifier in executing neurodevelopmental programs. Here, we find that PRC2 interacts with the nucleic acid-binding protein Ybx1. In the mouse embryo in vivo, Ybx1 is required for forebrain specification and restricting mid-hindbrain growth. In neural progenitor cells (NPCs), Ybx1 controls self-renewal and neuronal differentiation. Mechanistically, Ybx1 highly overlaps PRC2 binding genome-wide, controls PRC2 distribution, and inhibits H3K27me3 levels. These functions are consistent with Ybx1-mediated promotion of genes involved in forebrain specification, cell proliferation, or neuronal differentiation. In Ybx1-knockout NPCs, H3K27me3 reduction by PRC2 enzymatic inhibitor or genetic depletion partially rescues gene expression and NPC functions. Our findings suggest that Ybx1 fine-tunes PRC2 activities to regulate spatiotemporal gene expression in embryonic neural development and uncover a crucial epigenetic mechanism balancing forebrain-hindbrain lineages and self-renewal-differentiation choices in NPCs.
    DOI:  https://doi.org/10.1038/s41467-020-17878-y
  2. Genome Biol. 2020 Aug 07. 21(1): 198
    Integrative analyses of single-cell transcriptome and regulome using MAESTRO.
    Chenfei Wang, Dongqing Sun, Xin Huang, Changxin Wan, Ziyi Li, Ya Han, Qian Qin, Jingyu Fan, Xintao Qiu, Yingtian Xie, Clifford A Meyer, Myles Brown, Ming Tang, Henry Long, Tao Liu, X Shirley Liu.
      We present Model-based AnalysEs of Transcriptome and RegulOme (MAESTRO), a comprehensive open-source computational workflow ( http://github.com/liulab-dfci/MAESTRO ) for the integrative analyses of single-cell RNA-seq (scRNA-seq) and ATAC-seq (scATAC-seq) data from multiple platforms. MAESTRO provides functions for pre-processing, alignment, quality control, expression and chromatin accessibility quantification, clustering, differential analysis, and annotation. By modeling gene regulatory potential from chromatin accessibilities at the single-cell level, MAESTRO outperforms the existing methods for integrating the cell clusters between scRNA-seq and scATAC-seq. Furthermore, MAESTRO supports automatic cell-type annotation using predefined cell type marker genes and identifies driver regulators from differential scRNA-seq genes and scATAC-seq peaks.
    Keywords:  Cell-type annotation; Computational workflow; Integrate scRNA-seq and scATAC-seq; Predict transcriptional regulators; Single-cell ATAC-seq; Single-cell RNA-seq
    DOI:  https://doi.org/10.1186/s13059-020-02116-x
  3. Proc Natl Acad Sci U S A. 2020 Aug 10. pii: 201920499. [Epub ahead of print]
    Physical modeling of the heritability and maintenance of epigenetic modifications.
    Sarah H Sandholtz, Quinn MacPherson, Andrew J Spakowitz.
      We develop a predictive theoretical model of the physical mechanisms that govern the heritability and maintenance of epigenetic modifications. This model focuses on a particular modification, methylation of lysine-9 of histone H3 (H3K9), which is one of the most representative and critical epigenetic marks that affects chromatin organization and gene expression. Our model combines the effect of segregation and compaction on chromosomal organization with the effect of the interaction between proteins that compact the chromatin (heterochromatin protein 1) and the methyltransferases that affect methyl spreading. Our chromatin model demonstrates that a block of H3K9 methylations in the epigenetic sequence determines the compaction state at any particular location in the chromatin. Using our predictive model for chromatin compaction, we develop a methylation model to address the reestablishment of the methylation sequence following DNA replication. Our model reliably maintains methylation over generations, thereby establishing the robustness of the epigenetic code.
    Keywords:  Monte Carlo simulations; chromosome modeling; epigenetics; genome organization; heritability
    DOI:  https://doi.org/10.1073/pnas.1920499117
  4. Epigenetics. 2020 Aug 14.
    Deacetylation of H4 lysine16 affects acetylation of lysine residues in histone H3 and H4 and promotes transcription of constitutive genes.
    Anagh Ray, Preeti Khan, Ronita Nag Chaudhuri.
      Histone modification map of H4 N-terminal tail residues in Saccharomyces cerevisiae reveals the prominence of lysine acetylation. Previous reports have indicated the importance of lysine acetylation in maintaining chromatin structure and function. H4K16, a residue with highly regulated acetylation dynamics has unique functions not overlapping with the other H4 N- terminal acetylable residues. The present work unravels the role of H4K16 acetylation in regulating expression of constitutive genes. H4K16 gets distinctly deacetylated over the coding region of constitutively expressed genes. Deacetylation of H4K16 reduces H3K9 acetylation at the cellular and gene level. Reduced H3K9 acetylation however did not negatively correlate with active gene transcription. Significantly, H4K16 deacetylation was found to be associated with hypoacetylated H4K12 throughout the locus of constitutive genes. H4K16 and K12 deacetylation is known to favour active transcription. Sas2, the HAT mutant showed similar patterns of hypoacetylated H3K9 and H4K12 at the active loci, clearly implying that the modifications were associated with deacetylation state of H4K16. Deacetylation of H4K16 was also concurrent with increased H3K56 acetylation in the promoter region and ORF of the constitutive genes. Combination of all these histone modifications significantly reduced H3 occupancy, increased promoter accessibility and enhanced RNAPII recruitment at the constitutively active loci. Consequently, we found that expression of active genes was higher in H4K16R mutant which mimic deacetylated state, but not in H4K16Q mimicking constitutive acetylation. To summarize, H4K16 deacetylation linked with H4K12 and H3K9 hypoacetylation along with H3K56 hyperacetylation generate a chromatin landscape that is conducive for transcription of constitutive genes.
    Keywords:  H3K56; H3K9; H4K12; H4K16; constitutive genes; histone acetylation; transcription
    DOI:  https://doi.org/10.1080/15592294.2020.1809896
  5. Nat Genet. 2020 Aug 10.
    N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2.
    Yuan Li, Linjian Xia, Kaifen Tan, Xidong Ye, Zhixiang Zuo, Minchun Li, Rui Xiao, Zihan Wang, Xiaona Liu, Mingqiang Deng, Jinru Cui, Mengtian Yang, Qizhi Luo, Sun Liu, Xin Cao, Haoran Zhu, Tianqi Liu, Jiaxin Hu, Junfang Shi, Shan Xiao, Laixin Xia.
      A dynamic epigenome is critical for appropriate gene expression in development and health1-5. Central to this is the intricate process of transcription6-11, which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N6-methyladenosine (m6A), which is co-transcriptionally incorporated. The integration of these aspects of the dynamic epigenome, however, is not well understood mechanistically. Here we show that the repressive histone mark H3K9me2 is specifically removed by the induction of m6A-modified transcripts. We demonstrate that the methyltransferase METTL3/METTL14 regulates H3K9me2 modification. We observe a genome-wide correlation between m6A and occupancy by the H3K9me2 demethylase KDM3B, and we find that the m6A reader YTHDC1 physically interacts with and recruits KDM3B to m6A-associated chromatin regions, promoting H3K9me2 demethylation and gene expression. This study establishes a direct link between m6A and dynamic chromatin modification and provides mechanistic insight into the co-transcriptional interplay between RNA modifications and histone modifications.
    DOI:  https://doi.org/10.1038/s41588-020-0677-3
  6. Epigenetics Chromatin. 2020 Aug 10. 13(1): 32
    Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells.
    Nicole L Arruda, Zachary M Carico, Megan Justice, Ying Frances Liu, Junjie Zhou, Holden C Stefan, Jill M Dowen.
       BACKGROUND: The three-dimensional organization of the genome in the nucleus plays an integral role in many biological processes, including gene expression. The genome is folded into DNA loops that bring together distal regulatory elements and genes. Cohesin, a ring-shaped protein complex, is a major player in the formation of DNA loops. Cohesin is composed of a core trimer and one of two variant STAG subunits, STAG1 or STAG2. It is not understood whether variant STAG proteins give rise to cohesin complexes with distinct functions. Recent studies have begun to characterize the roles of STAG1 and STAG2, with partially contradictory results.
    RESULTS: Here, we generate stable single-knockout embryonic stem cell lines to investigate the individual contributions of STAG1 and STAG2 in regulating cohesin chromosomal localization and function. We report both overlapping roles for STAG1 and STAG2 in cohesin localization and somewhat distinct roles in gene expression. STAG1 and STAG2 occupy the same sites across the genome, yet do not exist together in a higher order complex. Despite their shared localization, STAG1 and STAG2 have both distinct and redundant effects on gene expression. Loss of both STAG1 and STAG2 causes widespread transcriptome dysregulation, altered cohesin DNA occupancy, and reduced cell proliferation.
    CONCLUSIONS: Together, this work reveals the requirement of at least one STAG protein for proper cohesin function. STAG1 and STAG2 have independent roles in cohesin localization and both overlapping and distinct roles in gene expression. The roles of STAG1 and STAG2 in mouse embryonic stem cells may be somewhat different than in other cell types, due to their relative expression levels. These results advance our understanding of the link between mammalian genome organization and gene expression during development and disease contexts.
    Keywords:  CRISPR/Cas9; CTCF; Cohesin; Enhancers; Gene expression; Promoters; STAG; Stem cell; Transcription
    DOI:  https://doi.org/10.1186/s13072-020-00353-9
  7. Sci Rep. 2020 Aug 12. 10(1): 13615
    Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential.
    Leah S VandenBosch, Stefanie G Wohl, Matthew S Wilken, Marcus Hooper, Connor Finkbeiner, Kristen Cox, Laura Chipman, Thomas A Reh.
      Diseases and damage to the retina lead to losses in retinal neurons and eventual visual impairment. Although the mammalian retina has no inherent regenerative capabilities, fish have robust regeneration from Müller glia (MG). Recently, we have shown that driving expression of Ascl1 in adult mouse MG stimulates neural regeneration. The regeneration observed in the mouse is limited in the variety of neurons that can be derived from MG; Ascl1-expressing MG primarily generate bipolar cells. To better understand the limits of MG-based regeneration in mouse retinas, we used ATAC- and RNA-seq to compare newborn progenitors, immature MG (P8-P12), and mature MG. Our analysis demonstrated developmental differences in gene expression and accessible chromatin between progenitors and MG, primarily in neurogenic genes. Overexpression of Ascl1 is more effective in reprogramming immature MG, than mature MG, consistent with a more progenitor-like epigenetic landscape in the former. We also used ASCL1 ChIPseq to compare the differences in ASCL1 binding in progenitors and reprogrammed MG. We find that bipolar-specific accessible regions are more frequently linked to bHLH motifs and ASCL1 binding. Overall, our analysis indicates a loss of neurogenic gene expression and motif accessibility during glial maturation that may prevent efficient reprogramming.
    DOI:  https://doi.org/10.1038/s41598-020-70334-1
  8. Cancer Res. 2020 Aug 11. pii: canres.0066.2020. [Epub ahead of print]
    YTHDF1 promotes gastric carcinogenesis by controlling translation of FZD7.
    Jingnan Pi, Wen Wang, Ming Ji, Xiaoshuang Wang, Xueju Wei, Jing Jin, Tao Liu, Jiaqi Qiang, Zhihong Qi, Feng Li, Yue Liu, Yanni Ma, Yanmin Si, Yue Huo, Yufeng Gao, Yiying Chen, Lei Dong, Rui Su, Jianjun Chen, Shuan Rao, Ping Yi, Shuyang Yu, Fang Wang, Jia Yu.
      N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here we aimed to investigate the role of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer (GC) tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of gastric cancer patients and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated GC cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyper-activation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0066
  9. Proc Natl Acad Sci U S A. 2020 Aug 10. pii: 202005500. [Epub ahead of print]
    Nucleosome allostery in pioneer transcription factor binding.
    Cheng Tan, Shoji Takada.
      While recent experiments revealed that some pioneer transcription factors (TFs) can bind to their target DNA sequences inside a nucleosome, the binding dynamics of their target recognitions are poorly understood. Here we used the latest coarse-grained models and molecular dynamics simulations to study the nucleosome-binding procedure of the two pioneer TFs, Sox2 and Oct4. In the simulations for a strongly positioning nucleosome, Sox2 selected its target DNA sequence only when the target was exposed. Otherwise, Sox2 entropically bound to the dyad region nonspecifically. In contrast, Oct4 plastically bound on the nucleosome mainly in two ways. First, the two POU domains of Oct4 separately bound to the two parallel gyres of the nucleosomal DNA, supporting the previous experimental results of the partial motif recognition. Second, the POUS domain of Oct4 favored binding on the acidic patch of histones. Then, simulating the TFs binding to a genomic nucleosome, the LIN28B nucleosome, we found that the recognition of a pseudo motif by Sox2 induced the local DNA bending and shifted the population of the rotational position of the nucleosomal DNA. The redistributed DNA phase, in turn, changed the accessibility of a distant TF binding site, which consequently affected the binding probability of a second Sox2 or Oct4. These results revealed a nucleosomal DNA-mediated allosteric mechanism, through which one TF binding event can change the global conformation, and effectively regulate the binding of another TF at distant sites. Our simulations provide insights into the binding mechanism of single and multiple TFs on the nucleosome.
    Keywords:  Oct4; Sox2; allostery; coarse-grained molecular dynamics; pioneer factor
    DOI:  https://doi.org/10.1073/pnas.2005500117
  10. Cell Rep. 2020 Aug 11. pii: S2211-1247(20)30988-8. [Epub ahead of print]32(6): 108003
    Differential Histone Distribution Patterns in Induced Asymmetrically Dividing Mouse Embryonic Stem Cells.
    Binbin Ma, Tung-Jui Trieu, Ji Cheng, Shuang Zhou, Qingsong Tang, Jing Xie, Ji-Long Liu, Keji Zhao, Shukry J Habib, Xin Chen.
      Wnt3a-coated beads can induce asymmetric divisions of mouse embryonic stem cells (mESCs), resulting in one self-renewed mESC and one differentiating epiblast stem cell. This provides an opportunity for studying histone inheritance pattern at a single-cell resolution in cell culture. Here, we report that mESCs with Wnt3a-bead induction display nonoverlapping preexisting (old) versus newly synthesized (new) histone H3 patterns, but mESCs without Wnt3a beads have largely overlapping patterns. Furthermore, H4K20me2/3, an old histone-enriched modification, displays a higher instance of asymmetric distribution on chromatin fibers from Wnt3a-induced mESCs than those from non-induced mESCs. These locally distinct distributions between old and new histones have both cellular specificity in Wnt3a-induced mESCs and molecular specificity for histones H3 and H4. Given that post-translational modifications at H3 and H4 carry the major histone modifications, our findings provide a mammalian cell culture system to study histone inheritance for maintaining stem cell fate and for resetting it during differentiation.
    Keywords:  Wnt3a beads; asymmetric cell division; histone; mouse embryonic stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2020.108003
  11. Cell Rep. 2020 Aug 11. pii: S2211-1247(20)30992-X. [Epub ahead of print]32(6): 108007
    Runx2+ Niche Cells Maintain Incisor Mesenchymal Tissue Homeostasis through IGF Signaling.
    Shuo Chen, Junjun Jing, Yuan Yuan, Jifan Feng, Xia Han, Quan Wen, Thach-Vu Ho, Chelsea Lee, Yang Chai.
      Stem cell niches provide a microenvironment to support the self-renewal and multi-lineage differentiation of stem cells. Cell-cell interactions within the niche are essential for maintaining tissue homeostasis. However, the niche cells supporting mesenchymal stem cells (MSCs) are largely unknown. Using single-cell RNA sequencing, we show heterogeneity among Gli1+ MSCs and identify a subpopulation of Runx2+/Gli1+ cells in the adult mouse incisor. These Runx2+/Gli1+ cells are strategically located between MSCs and transit-amplifying cells (TACs). They are not stem cells but help to maintain the MSC niche via IGF signaling to regulate TAC proliferation, differentiation, and incisor growth rate. ATAC-seq and chromatin immunoprecipitation reveal that Runx2 directly binds to Igfbp3 in niche cells. This Runx2-mediated IGF signaling is crucial for regulating the MSC niche and maintaining tissue homeostasis to support continuous growth of the adult mouse incisor, providing a model for analysis of the molecular regulation of the MSC niche.
    Keywords:  IGF signaling; Runx2; adult mouse incisor; growth rate; mesenchymal stem cells; niche; transit-amplifying cells
    DOI:  https://doi.org/10.1016/j.celrep.2020.108007
  12. Sci Adv. 2020 Jul;6(31): eabb2529
    NuRD mediates mitochondrial stress-induced longevity via chromatin remodeling in response to acetyl-CoA level.
    Di Zhu, Xueying Wu, Jun Zhou, Xinyu Li, Xiahe Huang, Jiasheng Li, Junbo Wu, Qian Bian, Yingchun Wang, Ye Tian.
      Mild mitochondrial stress experienced early in life can have beneficial effects on the life span of organisms through epigenetic regulations. Here, we report that acetyl-coenzyme A (CoA) represents a critical mitochondrial signal to regulate aging through the chromatin remodeling and histone deacetylase complex (NuRD) in Caenorhabditis elegans. Upon mitochondrial stress, the impaired tricarboxylic acid cycle results in a decreased level of citrate, which accounts for reduced production of acetyl-CoA and consequently induces nuclear accumulation of the NuRD and a homeodomain-containing transcription factor DVE-1, thereby enabling decreased histone acetylation and chromatin reorganization. The metabolic stress response is thus established during early life and propagated into adulthood to allow transcriptional regulation for life-span extension. Furthermore, adding nutrients to restore acetyl-CoA production is sufficient to counteract the chromatin changes and diminish the longevity upon mitochondrial stress. Our findings uncover the molecular mechanism of the metabolite-mediated epigenome for the regulation of organismal aging.
    DOI:  https://doi.org/10.1126/sciadv.abb2529
  13. Nat Rev Cancer. 2020 Aug 11.
    The epigenomics of sarcoma.
    Benjamin A Nacev, Kevin B Jones, Andrew M Intlekofer, Jamie S E Yu, C David Allis, William D Tap, Marc Ladanyi, Torsten O Nielsen.
      Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.
    DOI:  https://doi.org/10.1038/s41568-020-0288-4
  14. Nat Commun. 2020 Aug 13. 11(1): 4055
    Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis.
    Matthew E Bechard, Rana Smalling, Akimasa Hayashi, Yi Zhong, Anna E Word, Sydney L Campbell, Amanda V Tran, Vivian L Weiss, Christine Iacobuzio-Donahue, Kathryn E Wellen, Oliver G McDonald.
      Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.
    DOI:  https://doi.org/10.1038/s41467-020-17839-5
  15. Cancer Cell. 2020 Jul 30. pii: S1535-6108(20)30369-X. [Epub ahead of print]
    Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.
    Chan Chung, Stefan R Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee, Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian K Werner, Daniel R Wahl, Costas A Lyssiotis, Zhiguo Bian, J Brad Shotwell, Viveka Nand Yadav, Carl Koschmann, Arul M Chinnaiyan, Stefan Blüml, Alexander R Judkins, Sriram Venneti.
      H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.
    Keywords:  D-2HG; DIPG; H3K27me3; IDH mutation; epigenetics; glutaminolysis; glycolysis; histone methylation; histone mutation; metabolism; α-KG
    DOI:  https://doi.org/10.1016/j.ccell.2020.07.008
  16. Sci Adv. 2020 Jul;6(31): eaaw7313
    Functional definition of a transcription factor hierarchy regulating T cell lineage commitment.
    Laura Garcia-Perez, Farbod Famili, Martijn Cordes, Martijn Brugman, Marja van Eggermond, Haoyu Wu, Jihed Chouaref, David San León Granado, Machteld M Tiemessen, Karin Pike-Overzet, Lucia Daxinger, Frank J T Staal.
      T cell factor 1 (Tcf1) is the first T cell-specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell-committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.
    DOI:  https://doi.org/10.1126/sciadv.aaw7313
  17. Brief Bioinform. 2020 Aug 11. pii: bbaa162. [Epub ahead of print]
    SurvivalMeth: a web server to investigate the effect of DNA methylation-related functional elements on prognosis.
    Chunlong Zhang, Ning Zhao, Xue Zhang, Jun Xiao, Junyi Li, Dezhong Lv, Weiwei Zhou, Yongsheng Li, Juan Xu, Xia Li.
      Aberrant DNA methylation is a fundamental characterization of epigenetics for carcinogenesis. Abnormality of DNA methylation-related functional elements (DMFEs) may lead to dysfunction of regulatory genes in the progression of cancers, contributing to prognosis of many cancers. There is an urgent need to construct a tool to comprehensively assess the impact of DMFEs on prognosis. Therefore, we developed SurvivalMeth (http://bio-bigdata.hrbmu.edu.cn/survivalmeth) to explore the prognosis-related DMFEs, which documented many kinds of DMFEs, including 309,465 CpG island-related elements, 104,748 transcript-related elements, 77,634 repeat elements, as well as cell-type specific 1,689,653 super enhancers (SE) and 1,304,902 CTCF binding regions for analysis. SurvivalMeth is a convenient tool which collected DNA methylation profiles of 36 cancers and allowed users to query their genes of interest in different datasets for prognosis. Furthermore, SurvivalMeth not only integrated different combinations, including single DMFE, multiple DMFEs, SEs and clinical data, to perform survival analysis on preupload data but also allowed for uploading customized DNA methylation profile of DMFEs from various diseases to analyze. SurvivalMeth provided a comprehensive resource and automated analysis for prognostic DMFEs, including DMFE methylation level, correlation analysis, clinical analysis, differential analysis, DMFE annotation, survival-related detailed result and visualization of survival analysis. In summary, we believe that SurvivalMeth will facilitate prognostic research of DMFEs in diverse cancers.
    Keywords:  DNA methylation; SurvivalMeth; cancer; functional element; survival analysis; web server
    DOI:  https://doi.org/10.1093/bib/bbaa162
  18. Nat Commun. 2020 Aug 14. 11(1): 4083
    BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage.
    Fred C Lam, Yi Wen Kong, Qiuying Huang, Tu-Lan Vu Han, Amanda D Maffa, Ekkehard M Kasper, Michael B Yaffe.
      Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells.
    DOI:  https://doi.org/10.1038/s41467-020-17503-y
  19. Mol Cell. 2020 Jul 31. pii: S1097-2765(20)30469-X. [Epub ahead of print]
    Advances in Chromatin and Chromosome Research: Perspectives from Multiple Fields.
    Andrews Akwasi Agbleke, Assaf Amitai, Jason D Buenrostro, Aditi Chakrabarti, Lingluo Chu, Anders S Hansen, Kristen M Koenig, Ajay S Labade, Sirui Liu, Tadasu Nozaki, Sergey Ovchinnikov, Andrew Seeber, Haitham A Shaban, Jan-Hendrik Spille, Andrew D Stephens, Jun-Han Su, Dushan Wadduwage.
      Nucleosomes package genomic DNA into chromatin. By regulating DNA access for transcription, replication, DNA repair, and epigenetic modification, chromatin forms the nexus of most nuclear processes. In addition, dynamic organization of chromatin underlies both regulation of gene expression and evolution of chromosomes into individualized sister objects, which can segregate cleanly to different daughter cells at anaphase. This collaborative review shines a spotlight on technologies that will be crucial to interrogate key questions in chromatin and chromosome biology including state-of-the-art microscopy techniques, tools to physically manipulate chromatin, single-cell methods to measure chromatin accessibility, computational imaging with neural networks and analytical tools to interpret chromatin structure and dynamics. In addition, this review provides perspectives on how these tools can be applied to specific research fields such as genome stability and developmental biology and to test concepts such as phase separation of chromatin.
    DOI:  https://doi.org/10.1016/j.molcel.2020.07.003
  20. Sci Rep. 2020 Aug 07. 10(1): 13413
    Enhancing the interpretability of transcription factor binding site prediction using attention mechanism.
    Sungjoon Park, Yookyung Koh, Hwisang Jeon, Hyunjae Kim, Yoonsun Yeo, Jaewoo Kang.
      Transcription factors (TFs) regulate the gene expression of their target genes by binding to the regulatory sequences of target genes (e.g., promoters and enhancers). To fully understand gene regulatory mechanisms, it is crucial to decipher the relationships between TFs and DNA sequences. Moreover, studies such as GWAS and eQTL have verified that most disease-related variants exist in non-coding regions, and highlighted the necessity to identify such variants that cause diseases by interrupting TF binding mechanisms. To do this, it is necessary to build a prediction model that precisely predicts the binding relationships between TFs and DNA sequences. Recently, deep learning based models have been proposed and have shown competitive results on a transcription factor binding site prediction task. However, it is difficult to interpret the prediction results obtained from the previous models. In addition, the previous models assumed all the sequence regions in the input DNA sequence have the same importance for predicting TF-binding, although sequence regions containing TF-binding-associated signals such as TF-binding motifs should be captured more than other regions. To address these challenges, we propose TBiNet, an attention based interpretable deep neural network for predicting transcription factor binding sites. Using the attention mechanism, our method is able to assign more importance on the actual TF binding sites in the input DNA sequence. TBiNet outperforms the current state-of-the-art methods (DeepSea and DanQ) quantitatively in the TF-DNA binding prediction task. Moreover, TBiNet is more effective than the previous models in discovering known TF-binding motifs.
    DOI:  https://doi.org/10.1038/s41598-020-70218-4
  21. PLoS One. 2020 ;15(8): e0237403
    Dose-dependent regulation of horizontal cell fate by Onecut family of transcription factors.
    Michaela Kreplova, Andrea Kuzelova, Barbora Antosova, Lucie Zilova, Herbert Jägle, Zbynek Kozmik.
      Genome duplication leads to an emergence of gene paralogs that are essentially free to undergo the process of neofunctionalization, subfunctionalization or degeneration (gene loss). Onecut1 (Oc1) and Onecut2 (Oc2) transcription factors, encoded by paralogous genes in mammals, are expressed in precursors of horizontal cells (HCs), retinal ganglion cells and cone photoreceptors. Previous studies have shown that ablation of either Oc1 or Oc2 gene in the mouse retina results in a decreased number of HCs, while simultaneous deletion of Oc1 and Oc2 leads to a complete loss of HCs. Here we study the genetic redundancy between Oc1 and Oc2 paralogs and focus on how the dose of Onecut transcription factors influences abundance of individual retinal cell types and overall retina physiology. Our data show that reducing the number of functional Oc alleles in the developing retina leads to a gradual decrease in the number of HCs, progressive thinning of the outer plexiform layer and diminished electrophysiology responses. Taken together, these observations indicate that in the context of HC population, the alleles of Oc1/Oc2 paralogous genes are mutually interchangeable, function additively to support proper retinal function and their molecular evolution does not follow one of the typical routes after gene duplication.
    DOI:  https://doi.org/10.1371/journal.pone.0237403
  22. Cell Cycle. 2020 Aug 13. 1-10
    The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors.
    Swarnalatha Manickavinayaham, Renier Velez-Cruz, Anup K Biswas, Jie Chen, Ruifeng Guo, David G Johnson.
      The E2F1 transcription factor and RB tumor suppressor are best known for their roles in regulating the expression of genes important for cell cycle progression but, they also have transcription-independent functions that facilitate DNA repair at sites of damage. Depending on the type of DNA damage, E2F1 can recruit either the GCN5 or p300/CBP histone acetyltransferases to deposit different histone acetylation marks in flanking chromatin. At DNA double-strand breaks, E2F1 also recruits RB and the BRG1 ATPase to remodel chromatin and promote loading of the MRE11-RAD50-NBS1 complex. Knock-in mouse models demonstrate important roles for E2F1 post-translational modifications in regulating DNA repair and physiological responses to DNA damage. This review highlights how E2F1 moonlights in DNA repair, thus revealing E2F1 as a versatile protein that recruits many of the same chromatin-modifying enzymes to sites of DNA damage to promote repair that it recruits to gene promoters to regulate transcription.
    Keywords:  ATM/ATR; BRG1; E2F1; GCN5; TopBP1; p300/CBP
    DOI:  https://doi.org/10.1080/15384101.2020.1801190
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