bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2021–08–01
twenty-two papers selected by
Connor Rogerson, University of Cambridge, MRC Cancer Unit
  1. AnnoMiner is a new web-tool to integrate epigenetics, transcription factor occupancy and transcriptomics data to predict transcriptional regulators.
  2. Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.
  3. A BRD4-mediated elongation control point primes transcribing RNA polymerase II for 3'-processing and termination.
  4. Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin.
  5. CTCF chromatin residence time controls three-dimensional genome organization, gene expression and DNA methylation in pluripotent cells.
  6. In vivo analysis reveals that ATP-hydrolysis couples remodeling to SWI/SNF release from chromatin.
  7. VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer.
  8. Global patterns of enhancer activity during sea urchin embryogenesis assessed by eRNA profiling.
  9. Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
  10. Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function.
  11. Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity.
  12. Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.
  13. RECOGNICER: A coarse-graining approach for identifying broad domains from ChIP-seq data.
  14. scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse.
  15. HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways.
  16. Sensitivity of cohesin-chromatin association to high-salt treatment corroborates non-topological mode of loop extrusion.
  17. DeTOKI identifies and characterizes the dynamics of chromatin TAD-like domains in a single cell.
  18. Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages.
  19. Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis.
  20. Core promoter activity contributes to chromatin-based regulation of internal cryptic promoters.
  21. Parental methylome reprogramming in human uniparental blastocysts reveals germline memory transition.
  22. PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
  1. Sci Rep. 2021 Jul 29. 11(1): 15463
    AnnoMiner is a new web-tool to integrate epigenetics, transcription factor occupancy and transcriptomics data to predict transcriptional regulators.
    Arno Meiler, Fabio Marchiano, Margaux Haering, Manuela Weitkunat, Frank Schnorrer, Bianca H Habermann.
      Gene expression regulation requires precise transcriptional programs, led by transcription factors in combination with epigenetic events. Recent advances in epigenomic and transcriptomic techniques provided insight into different gene regulation mechanisms. However, to date it remains challenging to understand how combinations of transcription factors together with epigenetic events control cell-type specific gene expression. We have developed the AnnoMiner web-server, an innovative and flexible tool to annotate and integrate epigenetic, and transcription factor occupancy data. First, AnnoMiner annotates user-provided peaks with gene features. Second, AnnoMiner can integrate genome binding data from two different transcriptional regulators together with gene features. Third, AnnoMiner offers to explore the transcriptional deregulation of genes nearby, or within a specified genomic region surrounding a user-provided peak. AnnoMiner's fourth function performs transcription factor or histone modification enrichment analysis for user-provided gene lists by utilizing hundreds of public, high-quality datasets from ENCODE for the model organisms human, mouse, Drosophila and C. elegans. Thus, AnnoMiner can predict transcriptional regulators for a studied process without the strict need for chromatin data from the same process. We compared AnnoMiner to existing tools and experimentally validated several transcriptional regulators predicted by AnnoMiner to indeed contribute to muscle morphogenesis in Drosophila. AnnoMiner is freely available at http://chimborazo.ibdm.univ-mrs.fr/AnnoMiner/ .
    DOI:  https://doi.org/10.1038/s41598-021-94805-1
  2. FASEB J. 2021 08;35(8): e21781
    Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.
    Yujin Kang, Yea Woon Kim, Jin Kang, AeRi Kim.
      Histone H3K4me1 and H3K27ac are enhancer-specific modifications and are required for enhancers to activate transcription of target genes. However, the reciprocal effects of these histone modifications on each other and their roles in enhancers are not clear. Here to comparatively analyze the role of these modifications, we inhibited H3K4me1 and H3K27ac by deleting the SET domains of histone methyltransferases MLL3 and MLL4 and the HAT domain of histone acetyltransferase p300, respectively, in erythroid K562 cells. The loss of H3K4me1 reduced H3K27ac at the β-globin enhancer LCR HSs, but H3K27ac reduction did not affect H3K4me1. This unequal relationship between two modifications was revealed in putative enhancers by genome-wide analysis using ChIP-seq. Histone H3 eviction at putative enhancers was weakened by the loss of H3K4me1 but not by the loss of H3K27ac. Chromatin remodeling complexes were recruited into the β-globin LCR HSs in a H3K4me1-dependent manner. In contrast, H3K27ac was required for enhancer RNA (eRNA) transcription, and H3K4me1 was not enough for it. Forced H3K27ac-induced eRNA transcription without affecting H3K4me1 at the β-globin LCR HSs. These results indicate that H3K4me1 and H3K27ac affect each other in different ways and play more direct roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.
    Keywords:  H3K27ac; H3K4me1; eRNA transcription; enhancers; nucleosome eviction
    DOI:  https://doi.org/10.1096/fj.202100488R
  3. Mol Cell. 2021 Jul 22. pii: S1097-2765(21)00506-2. [Epub ahead of print]
    A BRD4-mediated elongation control point primes transcribing RNA polymerase II for 3'-processing and termination.
    Mirjam Arnold, Annkatrin Bressin, Olga Jasnovidova, David Meierhofer, Andreas Mayer.
      Transcription elongation has emerged as a regulatory hub in gene expression of metazoans. A major control point occurs during early elongation before RNA polymerase II (Pol II) is released into productive elongation. Prior research has linked BRD4 with transcription elongation. Here, we use rapid BET protein and BRD4-selective degradation along with quantitative genome-wide approaches to investigate direct functions of BRD4 in Pol II transcription regulation. Notably, as an immediate consequence of acute BRD4 loss, promoter-proximal pause release is impaired, and transcriptionally engaged Pol II past this checkpoint undergoes readthrough transcription. An integrated proteome-wide analysis uncovers elongation and 3'-RNA processing factors as core BRD4 interactors. BRD4 ablation disrupts the recruitment of general 3'-RNA processing factors at the 5'-control region, which correlates with RNA cleavage and termination defects. These studies, performed in human cells, reveal a BRD4-mediated checkpoint and begin to establish a molecular link between 5'-elongation control and 3'-RNA processing.
    Keywords:  3’-RNA processing; BET proteins; BRD4; PAF1 complex; RNA polymerase II; checkpoint; promoter-proximal pausing; readthrough; transcription elongation; transcription termination
    DOI:  https://doi.org/10.1016/j.molcel.2021.06.026
  4. Elife. 2021 Jul 27. pii: e69387. [Epub ahead of print]10
    Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin.
    Jee Min Kim, Pat Visanpattanasin, Vivian Jou, Sheng Liu, Xiaona Tang, Qinsi Zheng, Kai Yu Li, Jonathan Snedeker, Luke D Lavis, Timothee Lionnet, Carl Wu.
      Conserved ATP-dependent chromatin remodelers establish and maintain genome-wide chromatin architectures of regulatory DNA during cellular lifespan, but the temporal interactions between remodelers and chromatin targets have been obscure. We performed live-cell single-molecule tracking for RSC, SWI/SNF, CHD1, ISW1, ISW2, and INO80 remodeling complexes in budding yeast and detected hyperkinetic behaviors for chromatin-bound molecules that frequently transition to the free state for all complexes. Chromatin-bound remodelers display notably higher diffusion than nucleosomal histones, and strikingly fast dissociation kinetics with 4-7 s mean residence times. These enhanced dynamics require ATP binding or hydrolysis by the catalytic ATPase, uncovering an additional function to its established role in nucleosome remodeling. Kinetic simulations show that multiple remodelers can repeatedly occupy the same promoter region on a timescale of minutes, implicating an unending 'tug-of-war' that controls a temporally shifting window of accessibility for the transcription initiation machinery.
    Keywords:  S. cerevisiae; chromosomes; gene expression
    DOI:  https://doi.org/10.7554/eLife.69387
  5. Nat Cell Biol. 2021 Jul 29.
    CTCF chromatin residence time controls three-dimensional genome organization, gene expression and DNA methylation in pluripotent cells.
    Widia Soochit, Frank Sleutels, Gregoire Stik, Marek Bartkuhn, Sreya Basu, Silvia C Hernandez, Sarra Merzouk, Enrique Vidal, Ruben Boers, Joachim Boers, Michael van der Reijden, Bart Geverts, Wiggert A van Cappellen, Mirjam van den Hout, Zeliha Ozgur, Wilfred F J van IJcken, Joost Gribnau, Rainer Renkawitz, Thomas Graf, Adriaan Houtsmuller, Frank Grosveld, Ralph Stadhouders, Niels Galjart.
      The 11 zinc finger (ZF) protein CTCF regulates topologically associating domain formation and transcription through selective binding to thousands of genomic sites. Here, we replaced endogenous CTCF in mouse embryonic stem cells with green-fluorescent-protein-tagged wild-type or mutant proteins lacking individual ZFs to identify additional determinants of CTCF positioning and function. While ZF1 and ZF8-ZF11 are not essential for cell survival, ZF8 deletion strikingly increases the DNA binding off-rate of mutant CTCF, resulting in reduced CTCF chromatin residence time. Loss of ZF8 results in widespread weakening of topologically associating domains, aberrant gene expression and increased genome-wide DNA methylation. Thus, important chromatin-templated processes rely on accurate CTCF chromatin residence time, which we propose depends on local sequence and chromatin context as well as global CTCF protein concentration.
    DOI:  https://doi.org/10.1038/s41556-021-00722-w
  6. Elife. 2021 Jul 27. pii: e69424. [Epub ahead of print]10
    In vivo analysis reveals that ATP-hydrolysis couples remodeling to SWI/SNF release from chromatin.
    Ben Tilly, Gillian Chalkley, Jan van der Knaap, Yuri Moshkin, Tsung Wai Kan, Dick Hw Dekkers, Jeroen Demmers, Peter Verrijzer.
      ATP-dependent chromatin remodelers control the accessibility of genomic DNA through nucleosome mobilization. However, the dynamics of genome exploration by remodelers, and the role of ATP hydrolysis in this process remain unclear. We used live-cell imaging of Drosophila polytene nuclei to monitor Brahma (BRM) remodeler interactions with its chromosomal targets. In parallel, we measured local chromatin condensation and its effect on BRM association. Surprisingly, only a small portion of BRM is bound to chromatin at any given time. BRM binds decondensed chromatin but is excluded from condensed chromatin, limiting its genomic search space. BRM-chromatin interactions are highly dynamic, whereas histone-exchange is limited and much slower. Intriguingly, loss of ATP hydrolysis enhanced chromatin retention and clustering of BRM, which was associated with reduced histone turnover. Thus, ATP hydrolysis couples nucleosome remodeling to remodeler release, driving a continuous transient probing of the genome.
    Keywords:  D. melanogaster; biochemistry; chemical biology; chromosomes; gene expression
    DOI:  https://doi.org/10.7554/eLife.69424
  7. Mol Oncol. 2021 Jul 27.
    VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer.
    Nikhil Baban Ghate, Sangnam Kim, Erin Spiller, Sungmin Kim, Yonghwan Shin, Suhn K Rhie, Goar Smbatyan, Heinz-Josef Lenz, Shannon M Mumenthaler, Woojin An.
      Histone modification is aberrantly regulated in cancer and generates an unbalanced state of gene transcription. VprBP, a recently identified kinase, phosphorylates histone H2A on threonine 120 (T120) and is involved in oncogenic transcriptional dysregulation; however, its specific role in colon cancer is undefined. Here, we show that VprBP is overexpressed in colon cancer and directly contributes to epigenetic gene silencing and cancer pathogenesis. Mechanistically, the observed function of VprBP is mediated through H2AT120 phosphorylation (H2AT120p)-driven transcriptional repression of growth regulatory genes, resulting in a significantly higher proliferative capacity of colon cancer cells. Our preclinical studies using organoid and xenograft models demonstrate that treatment with the VprBP inhibitor B32B3 impairs colonic tumor growth by blocking H2AT120p and reactivating a transcriptional program resembling that of normal cells. Collectively, our work describes VprBP as a master kinase contributing to the development and progression of colon cancer, making it a new molecular target for novel therapeutic strategies.
    Keywords:  H2A; VprBP; chromatin; colon cancer; histone; phosphorylation; transcription
    DOI:  https://doi.org/10.1002/1878-0261.13068
  8. Genome Res. 2021 Jul 30. pii: gr.275684.121. [Epub ahead of print]
    Global patterns of enhancer activity during sea urchin embryogenesis assessed by eRNA profiling.
    Jian Ming Khor, Jennifer Guerrero-Santoro, William Douglas, Charles A Ettensohn.
      We used CAGE-seq (Capped Analysis of Gene Expression with Sequencing) to profile eRNA expression and enhancer activity during embryogenesis of a model echinoderm- the sea urchin, Strongylocentrotus purpuratus We identified >18,000 enhancers that were active in mature oocytes and developing embryos and documented a burst of enhancer activation during cleavage and early blastula stages. We found that a large fraction (73.8%) of all enhancers active during the first 48 hr of embryogenesis were hyperaccessible no later than the 128-cell stage, and possibly even earlier. Most enhancers were located near gene bodies and temporal patterns of eRNA expression tended to parallel those of nearby genes. Furthermore, enhancers near lineage-specific genes contained signatures of inputs from developmental gene regulatory networks deployed in those lineages. A large fraction (60%) of sea urchin enhancers previously shown to be active in transgenic reporter assays were associated with eRNA expression. Moreover, a large fraction (50%) of a representative subset of enhancers identified by eRNA profiling drove tissue-specific gene expression in isolation when tested by reporter assays. Our findings provide an atlas of developmental enhancers in a model sea urchin and support the utility of eRNA profiling as a tool for enhancer discovery and regulatory biology. The data generated in this study are available at Echinobase, the public database of information related to echinoderm genomics.
    DOI:  https://doi.org/10.1101/gr.275684.121
  9. PLoS Genet. 2021 Jul 27. 17(7): e1009708
    Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
    Brady G Strittmatter, Travis J Jerde, Peter C Hollenhorst.
      The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.
    DOI:  https://doi.org/10.1371/journal.pgen.1009708
  10. Cell Rep. 2021 Jul 27. pii: S2211-1247(21)00863-9. [Epub ahead of print]36(4): 109446
    Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function.
    Benjamin Bourgeois, Tianshu Gui, Diana Hoogeboom, Henry G Hocking, Gesa Richter, Emil Spreitzer, Martin Viertler, Klaus Richter, Tobias Madl, Boudewijn M T Burgering.
      Transcription factors harbor defined regulatory intrinsically disordered regions (IDRs), which raises the question of how they mediate binding to structured co-regulators and modulate their activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the disordered FOXO4 C-terminal region, which contains its transactivation domain, binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of β-catenin competes with the autoinhibitory interaction of the FOXO4 disordered region with its DNA-binding Forkhead domain, and thereby enhances FOXO4 transcriptional activity. Furthermore, we show that binding of the β-catenin inhibitor protein ICAT is compatible with FOXO4 binding to β-catenin, suggesting that ICAT acts as a molecular switch between anti-proliferative FOXO and pro-proliferative Wnt/TCF/LEF signaling. These data illustrate how the interplay of IDRs, post-translational modifications, and co-factor binding contribute to transcription factor function.
    Keywords:  FOXO signaling; ICAT; NMR spectroscopy; Wnt signaling; cancer; intrinsically disordered proteins; phosphorylation; post-translational modification; structural biology; β-catenin
    DOI:  https://doi.org/10.1016/j.celrep.2021.109446
  11. Nat Commun. 2021 07 29. 12(1): 4618
    Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity.
    Yi Zhang, Kyle Brown, Yucong Yu, Ziad Ibrahim, Mohamad Zandian, Hongwen Xuan, Steven Ingersoll, Thomas Lee, Christopher C Ebmeier, Jiuyang Liu, Daniel Panne, Xiaobing Shi, Xiaojun Ren, Tatiana G Kutateladze.
      The transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the histone acetyltransferase (HAT) domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histone H3 tail and DNA, and are amplified through binding of p300 to the nucleosome. The catalytic HAT activity of p300 is decreased due to occlusion of the active site in the phase separated droplets, a large portion of which co-localizes with chromatin regions enriched in H3K27me3. Our findings suggest a model in which p300 condensates can act as a storage pool of the protein with reduced HAT activity, allowing p300 to be compartmentalized and concentrated at poised or repressed chromatin regions.
    DOI:  https://doi.org/10.1038/s41467-021-24950-8
  12. Nat Commun. 2021 07 27. 12(1): 4560
    Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis.
    Mengfei Liu, Sheng Cao, Li He, Jinhang Gao, Juan P Arab, Huarui Cui, Weixia Xuan, Yandong Gao, Tejasav S Sehrawat, Feda H Hamdan, Meritxell Ventura-Cots, Josepmaria Argemi, William C K Pomerantz, Steven A Johnsen, Jeong-Heon Lee, Fei Gao, Tamas Ordog, Philippe Mathurin, Alexander Revzin, Ramon Bataller, Huihuang Yan, Vijay H Shah.
      Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.
    DOI:  https://doi.org/10.1038/s41467-021-24843-w
  13. Quant Biol. 2020 Dec 24. 8(4): 359-368
    RECOGNICER: A coarse-graining approach for identifying broad domains from ChIP-seq data.
    Chongzhi Zang, Yiren Wang, Weiqun Peng.
       Background: Histone modifications are major factors that define chromatin states and have functions in regulating gene expression in eukaryotic cells. Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) technique has been widely used for profiling the genome-wide distribution of chromatin-associating protein factors. Some histone modifications, such as H3K27me3 and H3K9me3, usually mark broad domains in the genome ranging from kilobases (kb) to megabases (Mb) long, resulting in diffuse patterns in the ChIP-seq data that are challenging for signal separation. While most existing ChIP-seq peak-calling algorithms are based on local statistical models without account of multi-scale features, a principled method to identify scale-free board domains has been lacking.
    Methods: Here we present RECOGNICER (Recursive coarse-graining identification for ChIP-seq enriched regions), a computational method for identifying ChIP-seq enriched domains on a large range of scales. The algorithm is based on a coarse-graining approach, which uses recursive block transformations to determine spatial clustering of local enriched elements across multiple length scales.
    Results: We apply RECOGNICER to call H3K27me3 domains from ChIP-seq data, and validate the results based on H3K27me3's association with repressive gene expression. We show that RECOGNICER outperforms existing ChIP-seq broad domain calling tools in identifying more whole domains than separated pieces.
    Conclusion: RECOGNICER can be a useful bioinformatics tool for next-generation sequencing data analysis in epigenomics research.
    Keywords:  ChIP-seq; coarse-graining; histone modification; peak calling
    DOI:  https://doi.org/10.1007/s40484-020-0225-2
  14. Development. 2021 Jul 15. pii: dev196022. [Epub ahead of print]148(14):
    scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse.
    Marie-Theres Wittmann, Sayako Katada, Elisabeth Sock, Philipp Kirchner, Arif B Ekici, Michael Wegner, Kinichi Nakashima, Dieter Chichung Lie, André Reis.
      Transcription factor 4 (TCF4) is a crucial regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability and schizophrenia. As a class I bHLH transcription factor (TF), it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify TF partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs, we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implicated in this process. In addition to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TF networks in neurodevelopmental processes.
    Keywords:  Commissure development; Gene regulatory networks; Mouse; Protein-protein interaction; SOX11; Single-cell RNA sequencing; TCF4
    DOI:  https://doi.org/10.1242/dev.196022
  15. Elife. 2021 Jul 26. pii: e64148. [Epub ahead of print]10
    HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways.
    Ryo Miyamoto, Akinori Kanai, Hiroshi Okuda, Yosuke Komata, Satoshi Takahashi, Hirotaka Matsui, Toshiya Inaba, Akihiko Yokoyama.
      HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, BCL2 and SOX4 synergistically induced leukemia with MYC. Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias.
    Keywords:  HOXA9; MYC; apoptosis; cancer biology; chromosomes; gene expression; leukemia; mouse; transcription
    DOI:  https://doi.org/10.7554/eLife.64148
  16. Epigenetics Chromatin. 2021 Jul 28. 14(1): 36
    Sensitivity of cohesin-chromatin association to high-salt treatment corroborates non-topological mode of loop extrusion.
    Arkadiy K Golov, Anastasia V Golova, Alexey A Gavrilov, Sergey V Razin.
      Cohesin is a key organizer of chromatin folding in eukaryotic cells. The two main activities of this ring-shaped protein complex are the maintenance of sister chromatid cohesion and the establishment of long-range DNA-DNA interactions through the process of loop extrusion. Although the basic principles of both cohesion and loop extrusion have been described, we still do not understand several crucial mechanistic details. One of such unresolved issues is the question of whether a cohesin ring topologically embraces DNA string(s) during loop extrusion. Here, we show that cohesin complexes residing on CTCF-occupied genomic sites in mammalian cells do not interact with DNA topologically. We assessed the stability of cohesin-dependent loops and cohesin association with chromatin in high-ionic-strength conditions in G1-synchronized HeLa cells. We found that increased salt concentration completely displaces cohesin from those genomic regions that correspond to CTCF-defined loop anchors. Unsurprisingly, CTCF-anchored cohesin loops also dissipate in these conditions. Because topologically engaged cohesin is considered to be salt resistant, our data corroborate a non-topological model of loop extrusion. We also propose a model of cohesin activity throughout the interphase, which essentially equates the termination of non-topological loop extrusion with topological loading of cohesin. This theoretical framework enables a parsimonious explanation of various seemingly contradictory experimental findings.
    Keywords:  CTCF; Chromatin folding; Cohesin; Loop extrusion; Topological entrapment
    DOI:  https://doi.org/10.1186/s13072-021-00411-w
  17. Genome Biol. 2021 Jul 27. 22(1): 217
    DeTOKI identifies and characterizes the dynamics of chromatin TAD-like domains in a single cell.
    Xiao Li, Guangjie Zeng, Angsheng Li, Zhihua Zhang.
      Topologically associating domains (TAD) are a key structure of the 3D mammalian genomes. However, the prevalence and dynamics of TAD-like domains in single cells remain elusive. Here we develop a new algorithm, named deTOKI, to decode TAD-like domains with single-cell Hi-C data. By non-negative matrix factorization, deTOKI seeks regions that insulate the genome into blocks with minimal chance of clustering. deTOKI outperforms competing tools and reliably identifies TAD-like domains in single cells. Finally, we find that TAD-like domains are not only prevalent, but also subject to tight regulation in single cells.
    Keywords:  3D genome; Hi-C; Single cell; TAD
    DOI:  https://doi.org/10.1186/s13059-021-02435-7
  18. Cell Death Dis. 2021 Jul 27. 12(8): 743
    Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages.
    Ye Hu, Xin Wang, Jiaying Song, Jiacheng Wu, Jia Xu, Yangyang Chai, Yuanyuan Ding, Bingjing Wang, Chunmei Wang, Yong Zhao, Zhongyang Shen, Xiaoqing Xu, Xuetao Cao.
      Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.
    DOI:  https://doi.org/10.1038/s41419-021-04032-9
  19. Nucleic Acids Res. 2021 Jul 28. pii: gkab633. [Epub ahead of print]
    Characterization of a functional endothelial super-enhancer that regulates ADAMTS18 and angiogenesis.
    Isidore Mushimiyimana, Henri Niskanen, Mustafa Beter, Johanna P Laakkonen, Minna U Kaikkonen, Seppo Ylä-Herttuala, Nihay Laham-Karam.
      Super-enhancers are clusters of enhancers associated with cell lineage. They can be powerful gene-regulators and may be useful in cell-type specific viral-vector development. Here, we have screened for endothelial super-enhancers and identified an enhancer from within a cluster that conferred 5-70-fold increase in transgene expression. Importantly, CRISPR/Cas9 deletion of enhancers demonstrated regulation of ADAMTS18, corresponding to evidence of chromatin contacts between these genomic regions. Cell division-related pathways were primarily affected by the enhancer deletions, which correlated with significant reduction in cell proliferation. Furthermore, we observed changes in angiogenesis-related genes consistent with the endothelial specificity of this SE. Indeed, deletion of the enhancers affected tube formation, resulting in reduced or shortened sprouts. The super-enhancer angiogenic role is at least partly due to its regulation of ADAMTS18, as siRNA knockdown of ADAMTS18 resulted in significantly shortened endothelial sprouts. Hence, functional characterization of a novel endothelial super-enhancer has revealed substantial downstream effects from single enhancer deletions and led to the discovery of the cis-target gene ADAMTS18 and its role in endothelial function.
    DOI:  https://doi.org/10.1093/nar/gkab633
  20. Nucleic Acids Res. 2021 Jul 28. pii: gkab639. [Epub ahead of print]
    Core promoter activity contributes to chromatin-based regulation of internal cryptic promoters.
    Bo Bae Lee, Hyeonju Woo, Min Kyung Lee, SeoJung Youn, Sumin Lee, Jae-Seok Roe, Soo Young Lee, TaeSoo Kim.
      During RNA polymerase II (RNA Pol II) transcription, the chromatin structure undergoes dynamic changes, including opening and closing of the nucleosome to enhance transcription elongation and fidelity. These changes are mediated by transcription elongation factors, including Spt6, the FACT complex, and the Set2-Rpd3S HDAC pathway. These factors not only contribute to RNA Pol II elongation, reset the repressive chromatin structures after RNA Pol II has passed, thereby inhibiting aberrant transcription initiation from the internal cryptic promoters within gene bodies. Notably, the internal cryptic promoters of infrequently transcribed genes are sensitive to such chromatin-based regulation but those of hyperactive genes are not. To determine why, the weak core promoters of genes that generate cryptic transcripts in cells lacking transcription elongation factors (e.g. STE11) were replaced with those from more active genes. Interestingly, as core promoter activity increased, activation of internal cryptic promoter dropped. This associated with loss of active histone modifications at the internal cryptic promoter. Moreover, environmental changes and transcription elongation factor mutations that downregulated the core promoters of highly active genes concomitantly increased their cryptic transcription. We therefore propose that the chromatin-based regulation of internal cryptic promoters is mediated by core promoter strength as well as transcription elongation factors.
    DOI:  https://doi.org/10.1093/nar/gkab639
  21. Genome Res. 2021 Jul 30. pii: gr.273318.120. [Epub ahead of print]
    Parental methylome reprogramming in human uniparental blastocysts reveals germline memory transition.
    Jiawei Xu, Yimin Shu, Guidong Yao, Yu Zhang, Wenbin Niu, Yile Zhang, Xueshan Ma, Haixia Jin, Fuli Zhang, Senlin Shi, Yang Wang, Wenyan Song, Shanjun Dai, Luyao Cheng, Xiangyang Zhang, Wei Xie, Aaron J Hsueh, Yingpu Sun.
      Uniparental embryos derived from only the mother (gynogenetic, GG) or the father (androgenetic, AG) are unique models for studying genomic imprinting and parental contributions to embryonic development. Human parthenogenetic embryos can be obtained following artificial activation of unfertilized oocytes, but the production of AG embryos by injection of two sperm into one denucleated oocyte leads to an extra centriole, resulting in multipolar spindles, abnormal cell division, and developmental defects. Here, we improved androgenote production by transferring the male pronucleus from one zygote into another haploid androgenote to prevent extra centrioles and successfully generated human diploid androgenetic embryos capable of developing into blastocysts with an identifiable inner cell mass (ICM) and trophectoderm (TE). The GG embryos were also generated. The zygotic genome was successfully activated in both the AG and GG embryos. DNA methylome analysis showed that the GG blastocysts partially retain the oocyte transcription-dependent methylation pattern, whereas the AG blastocyst methylome showed more extensive demethylation. The methylation states of most known imprinted differentially methylated regions (DMRs) were recapitulated in the AG and GG blastocysts. Novel candidate imprinted DMRs were also identified. The production of uniparental human embryos followed by transcriptome and methylome analysis is valuable for identifying parental contributions and epigenome memory transitions during early human development.
    DOI:  https://doi.org/10.1101/gr.273318.120
  22. Nat Commun. 2021 Jul 30. 12(1): 4626
    PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
    Virginia Giuliani, Meredith A Miller, Chiu-Yi Liu, Stella R Hartono, Caleb A Class, Christopher A Bristow, Erika Suzuki, Lionel A Sanz, Guang Gao, Jason P Gay, Ningping Feng, Johnathon L Rose, Hideo Tomihara, Joseph R Daniele, Michael D Peoples, Jennifer P Bardenhagen, Mary K Geck Do, Qing E Chang, Bhavatarini Vangamudi, Christopher Vellano, Haoqiang Ying, Angela K Deem, Kim-Anh Do, Giannicola Genovese, Joseph R Marszalek, Jeffrey J Kovacs, Michael Kim, Jason B Fleming, Ernesto Guccione, Andrea Viale, Anirban Maitra, M Emilia Di Francesco, Timothy A Yap, Philip Jones, Giulio Draetta, Alessandro Carugo, Frederic Chedin, Timothy P Heffernan.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.
    DOI:  https://doi.org/10.1038/s41467-021-24798-y
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