bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024‒04‒07
seventeen papers selected by
Connor Rogerson, University of Cambridge
  1. Early neural specification of stem cells is mediated by a set of SOX2-dependent neural-associated enhancers.
  2. p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.
  3. Transcriptional elongation control of hypoxic response.
  4. MLL4 binds TET3.
  5. Systematic mapping of TF-mediated cell fate changes by a pooled induction coupled with scRNA-seq and multi-omics approaches.
  6. Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.
  7. Structural basis of Integrator-dependent RNA polymerase II termination.
  8. ETV2 induces endothelial, but not hematopoietic, lineage specification in birds.
  9. SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer.
  10. 14-3-3 binding motif phosphorylation disrupts Hdac4-organized condensates to stimulate cardiac reprogramming.
  11. Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells.
  12. DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability.
  13. Defective transfer of parental histone decreases frequency of homologous recombination by increasing free histone pools in budding yeast.
  14. Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.
  15. Iterative oxidation by TET1 is required for reprogramming of imprinting control regions and patterning of mouse sperm hypomethylated regions.
  16. Genome-scale chromatin binding dynamics of RNA Polymerase II general transcription machinery components.
  17. A senescence restriction point acting on chromatin integrates oncogenic signals.
  1. Stem Cell Reports. 2024 Mar 21. pii: S2213-6711(24)00078-X. [Epub ahead of print]
    Early neural specification of stem cells is mediated by a set of SOX2-dependent neural-associated enhancers.
    Pavel Tsaytler, Gaby Blaess, Manuela Scholze-Wittler, Frederic Koch, Bernhard G Herrmann.
      SOX2 is a transcription factor involved in the regulatory network maintaining the pluripotency of embryonic stem cells in culture as well as in early embryos. In addition, SOX2 plays a pivotal role in neural stem cell formation and neurogenesis. How SOX2 can serve both processes has remained elusive. Here, we identified a set of SOX2-dependent neural-associated enhancers required for neural lineage priming. They form a distinct subgroup (1,898) among 8,531 OCT4/SOX2/NANOG-bound enhancers characterized by enhanced SOX2 binding and chromatin accessibility. Activation of these enhancers is triggered by neural induction of wild-type cells or by default in Smad4-ablated cells resistant to mesoderm induction and is antagonized by mesodermal transcription factors via Sox2 repression. Our data provide mechanistic insight into the transition from the pluripotency state to the early neural fate and into the regulation of early neural versus mesodermal specification in embryonic stem cells and embryos.
    Keywords:  Sox2; default neurogenesis; differentiation; embryonic stem cells; enhancers; lineage choice; mesoderm; neural induction
    DOI:  https://doi.org/10.1016/j.stemcr.2024.03.003
  2. Nat Commun. 2024 Apr 01. 15(1): 2821
    p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.
    François Serra, Andrea Nieto-Aliseda, Lucía Fanlo-Escudero, Llorenç Rovirosa, Mónica Cabrera-Pasadas, Aleksey Lazarenkov, Blanca Urmeneta, Alvaro Alcalde-Merino, Emanuele M Nola, Andrei L Okorokov, Peter Fraser, Mariona Graupera, Sandra D Castillo, Jose L Sardina, Alfonso Valencia, Biola M Javierre.
      Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.
    DOI:  https://doi.org/10.1038/s41467-024-46666-1
  3. Proc Natl Acad Sci U S A. 2024 Apr 09. 121(15): e2321502121
    Transcriptional elongation control of hypoxic response.
    Shimaa Hassan AbdelAziz Soliman, Marta Iwanaszko, Bin Zheng, Sarah Gold, Benjamin Charles Howard, Madhurima Das, Ram Prosad Chakrabarty, Navdeep S Chandel, Ali Shilatifard.
      The release of paused RNA polymerase II (RNAPII) from promoter-proximal regions is tightly controlled to ensure proper regulation of gene expression. The elongation factor PTEF-b is known to release paused RNAPII via phosphorylation of the RNAPII C-terminal domain by its cyclin-dependent kinase component, CDK9. However, the signal and stress-specific roles of the various RNAPII-associated macromolecular complexes containing PTEF-b/CDK9 are not yet clear. Here, we identify and characterize the CDK9 complex required for transcriptional response to hypoxia. Contrary to previous reports, our data indicate that a CDK9 complex containing BRD4 but not AFF1/4 is essential for this hypoxic stress response. We demonstrate that BRD4 bromodomains (BET) are dispensable for the release of paused RNAPII at hypoxia-activated genes and that BET inhibition by JQ1 is insufficient to impair hypoxic gene response. Mechanistically, we demonstrate that the C-terminal region of BRD4 is required for Polymerase-Associated Factor-1 Complex (PAF1C) recruitment to establish an elongation-competent RNAPII complex at hypoxia-responsive genes. PAF1C disruption using a small-molecule inhibitor (iPAF1C) impairs hypoxia-induced, BRD4-mediated RNAPII release. Together, our results provide insight into potentially targetable mechanisms that control the hypoxia-responsive transcriptional elongation.
    Keywords:  RNA polymerase II; chromatin; epigenetic mechanisms; gene expression; transcription
    DOI:  https://doi.org/10.1073/pnas.2321502121
  4. Structure. 2024 Mar 27. pii: S0969-2126(24)00087-X. [Epub ahead of print]
    MLL4 binds TET3.
    Dustin C Becht, Sk Abdul Mohid, Ji-Eun Lee, Mohamad Zandian, Caroline Benz, Soumi Biswas, Vikrant Kumar Sinha, Ylva Ivarsson, Kai Ge, Yi Zhang, Tatiana G Kutateladze.
      Human mixed lineage leukemia 4 (MLL4), also known as KMT2D, regulates cell type specific transcriptional programs through enhancer activation. Along with the catalytic methyltransferase domain, MLL4 contains seven less characterized plant homeodomain (PHD) fingers. Here, we report that the sixth PHD finger of MLL4 (MLL4PHD6) binds to the hydrophobic motif of ten-eleven translocation 3 (TET3), a dioxygenase that converts methylated cytosine into oxidized derivatives. The solution NMR structure of the TET3-MLL4PHD6 complex and binding assays show that, like histone H4 tail, TET3 occupies the hydrophobic site of MLL4PHD6, and that this interaction is conserved in the seventh PHD finger of homologous MLL3 (MLL3PHD7). Analysis of genomic localization of endogenous MLL4 and ectopically expressed TET3 in mouse embryonic stem cells reveals a high degree overlap on active enhancers and suggests a potential functional relationship of MLL4 and TET3.
    Keywords:  MLL4; PHD finger; TET3; interaction; structure
    DOI:  https://doi.org/10.1016/j.str.2024.03.005
  5. Genome Res. 2024 Apr 05.
    Systematic mapping of TF-mediated cell fate changes by a pooled induction coupled with scRNA-seq and multi-omics approaches.
    Muyoung Lee, Qingqing Guo, Mijeong Kim, Joonhyuk Choi, Alia Segura, Alper Genceroglu, Lucy LeBlanc, Nereida Ramirez, Yu Jin Jang, Yeejin Jang, Bum-Kyu Lee, Edward M Marcotte, Jonghwan Kim.
      Transcriptional regulation controls cellular functions through interactions between transcription factors (TFs) and their chromosomal targets. However, understanding the fate conversion potential of multiple TFs in an inducible manner remains limited. Here, we introduce iTF-seq as a method for identifying individual TFs that can alter cell fate toward specific lineages at a single-cell level. iTF-seq enables time course monitoring of transcriptome changes, and with biotinylated individual TFs, it provides a multi-omics approach to understanding the mechanisms behind TF-mediated cell fate changes. Our iTF-seq study in mouse embryonic stem cells identified multiple TFs that trigger rapid transcriptome changes indicative of differentiation within a day of induction. Moreover, cells expressing these potent TFs often show a slower cell cycle and increased cell death. Further analysis using bioChIP-seq revealed that GCM1 and OTX2 act as pioneer factors and activators by increasing gene accessibility and activating the expression of lineage specification genes during cell fate conversion. iTF-seq has utility in both mapping cell fate conversion and understanding cell fate conversion mechanisms.
    DOI:  https://doi.org/10.1101/gr.277926.123
  6. Nat Commun. 2024 Apr 05. 15(1): 2960
    Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.
    Kosuke Yamaguchi, Xiaoying Chen, Brianna Rodgers, Fumihito Miura, Pavel Bashtrykov, Frédéric Bonhomme, Catalina Salinas-Luypaert, Deis Haxholli, Nicole Gutekunst, Bihter Özdemir Aygenli, Laure Ferry, Olivier Kirsh, Marthe Laisné, Andrea Scelfo, Enes Ugur, Paola B Arimondo, Heinrich Leonhardt, Masato T Kanemaki, Till Bartke, Daniele Fachinetti, Albert Jeltsch, Takashi Ito, Pierre-Antoine Defossez.
      DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.
    DOI:  https://doi.org/10.1038/s41467-024-47314-4
  7. Nature. 2024 Apr 03.
    Structural basis of Integrator-dependent RNA polymerase II termination.
    Isaac Fianu, Moritz Ochmann, James L Walshe, Olexandr Dybkov, Joseph Neos Cruz, Henning Urlaub, Patrick Cramer.
      The Integrator complex can terminate RNA polymerase II (Pol II) in the promoter-proximal region of genes. Previous work has shed light on how Integrator binds to the paused elongation complex consisting of Pol II, the DRB sensitivity-inducing factor (DSIF) and the negative elongation factor (NELF) and how it cleaves the nascent RNA transcript1, but has not explained how Integrator removes Pol II from the DNA template. Here we present three cryo-electron microscopy structures of the complete Integrator-PP2A complex in different functional states. The structure of the pre-termination complex reveals a previously unresolved, scorpion-tail-shaped INTS10-INTS13-INTS14-INTS15 module that may use its 'sting' to open the DSIF DNA clamp and facilitate termination. The structure of the post-termination complex shows that the previously unresolved subunit INTS3 and associated sensor of single-stranded DNA complex (SOSS) factors prevent Pol II rebinding to Integrator after termination. The structure of the free Integrator-PP2A complex in an inactive closed conformation2 reveals that INTS6 blocks the PP2A phosphatase active site. These results lead to a model for how Integrator terminates Pol II transcription in three steps that involve major rearrangements.
    DOI:  https://doi.org/10.1038/s41586-024-07269-4
  8. Life Sci Alliance. 2024 Jun;pii: e202402694. [Epub ahead of print]7(6):
    ETV2 induces endothelial, but not hematopoietic, lineage specification in birds.
    Wei Weng, Yuan Deng, Ruslan Deviatiiarov, Sofiane Hamidi, Eriko Kajikawa, Oleg Gusev, Hiroshi Kiyonari, Guojie Zhang, Guojun Sheng.
      Cardiovascular system develops from the lateral plate mesoderm. Its three primary cell lineages (hematopoietic, endothelial, and muscular) are specified by the sequential actions of conserved transcriptional factors. ETV2, a master regulator of mammalian hemangioblast development, however, is absent in the chicken genome and acts downstream of NPAS4L in zebrafish. Here, we investigated the epistatic relationship between NPAS4L and ETV2 in avian hemangioblast development. We showed that ETV2 is deleted in all 363 avian genomes analyzed. Mouse ETV2 induced LMO2, but not NPAS4L or SCL, expression in chicken mesoderm. Squamate (lizards, geckos, and snakes) genomes contain both NPAS4L and ETV2 In Madagascar ground gecko, both genes were expressed in developing hemangioblasts. Gecko ETV2 induced only LMO2 in chicken mesoderm. We propose that both NPAS4L and ETV2 were present in ancestral amniote, with ETV2 acting downstream of NPAS4L in endothelial lineage specification. ETV2 may have acted as a pioneer factor by promoting chromatin accessibility of endothelial-specific genes and, in parallel with NPAS4L loss in ancestral mammals, has gained similar function in regulating blood-specific genes.
    DOI:  https://doi.org/10.26508/lsa.202402694
  9. Nucleic Acids Res. 2024 Mar 30. pii: gkae206. [Epub ahead of print]
    SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer.
    Noora Leppänen, Heidi Kaljunen, Eerika Takala, Roosa Kaarijärvi, Petri I Mäkinen, Seppo Ylä-Herttuala, Ilkka Paatero, Ville Paakinaho, Kirsi Ketola.
      The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting in resistance to AR-targeted therapies. In this study, we examined the chromatin landscape of AR-positive prostate cancer cells post-exposure to the AR inhibitor enzalutamide. We identified a novel regulator of cell plasticity, the homeobox transcription factor SIX2, whose motif is enriched in accessible chromatin regions after treatment. Depletion of SIX2 in androgen-independent PC-3 prostate cancer cells induced a switch from a stem-like to an epithelial state, resulting in reduced cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects were mediated through the downregulation of the Wnt/β-catenin signalling pathway and subsequent reduction of nuclear β-catenin. Collectively, our findings provide compelling evidence that the depletion of SIX2 may represent a promising strategy for overcoming the cell plasticity mechanisms driving antiandrogen resistance in prostate cancer.
    DOI:  https://doi.org/10.1093/nar/gkae206
  10. Cell Rep. 2024 Apr 04. pii: S2211-1247(24)00382-6. [Epub ahead of print]43(4): 114054
    14-3-3 binding motif phosphorylation disrupts Hdac4-organized condensates to stimulate cardiac reprogramming.
    Liu Liu, Ienglam Lei, Shuo Tian, Wenbin Gao, Yijing Guo, Zhaokai Li, Ziad Sabry, Paul Tang, Y Eugene Chen, Zhong Wang.
      Cell fate conversion is associated with extensive post-translational modifications (PTMs) and architectural changes of sub-organelles, yet how these events are interconnected remains unknown. We report here the identification of a phosphorylation code in 14-3-3 binding motifs (PC14-3-3) that greatly stimulates induced cardiomyocyte (iCM) formation from fibroblasts. PC14-3-3 is identified in pivotal functional proteins for iCM reprogramming, including transcription factors and chromatin modifiers. Akt1 kinase and protein phosphatase 2A are the key writer and key eraser of the PC14-3-3 code, respectively. PC14-3-3 activation induces iCM formation with the presence of only Tbx5. In contrast, PC14-3-3 inhibition by mutagenesis or inhibitor-mediated code removal abolishes reprogramming. We discover that key PC14-3-3-embedded factors, such as histone deacetylase 4 (Hdac4), Mef2c, and Foxo1, form Hdac4-organized inhibitory nuclear condensates. PC14-3-3 activation disrupts Hdac4 condensates to promote cardiac gene expression. Our study suggests that sub-organelle dynamics regulated by a PTM code could be a general mechanism for stimulating cell reprogramming.
    Keywords:  14-3-3; CP: Molecular biology; biomolecular condensate; cardiac reprogramming; epigenetic code; post-translational modification
    DOI:  https://doi.org/10.1016/j.celrep.2024.114054
  11. Dev Cell. 2024 Apr 01. pii: S1534-5807(24)00143-6. [Epub ahead of print]
    Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells.
    Jonas L Fowler, Sherry Li Zheng, Alana Nguyen, Angela Chen, Xiaochen Xiong, Timothy Chai, Julie Y Chen, Daiki Karigane, Allison M Banuelos, Kouta Niizuma, Kensuke Kayamori, Toshinobu Nishimura, M Kyle Cromer, David Gonzalez-Perez, Charlotte Mason, Daniel Dan Liu, Leyla Yilmaz, Lucile Miquerol, Matthew H Porteus, Vincent C Luca, Ravindra Majeti, Hiromitsu Nakauchi, Kristy Red-Horse, Irving L Weissman, Lay Teng Ang, Kyle M Loh.
      The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.
    Keywords:  artery; developmental biology; hematopoietic stem cell; human pluripotent stem cell differentiation
    DOI:  https://doi.org/10.1016/j.devcel.2024.03.003
  12. Mol Cell. 2024 Mar 26. pii: S1097-2765(24)00188-6. [Epub ahead of print]
    DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability.
    Jin-Dong Hao, Qian-Lan Liu, Meng-Xia Liu, Xing Yang, Liu-Ming Wang, Si-Yi Su, Wen Xiao, Meng-Qi Zhang, Yi-Chang Zhang, Lan Zhang, Yu-Sheng Chen, Yun-Gui Yang, Jie Ren.
      N6-methyladenosine (m6A) is a crucial RNA modification that regulates diverse biological processes in human cells, but its co-transcriptional deposition and functions remain poorly understood. Here, we identified the RNA helicase DDX21 with a previously unrecognized role in directing m6A modification on nascent RNA for co-transcriptional regulation. DDX21 interacts with METTL3 for co-recruitment to chromatin through its recognition of R-loops, which can be formed co-transcriptionally as nascent transcripts hybridize onto the template DNA strand. Moreover, DDX21's helicase activity is needed for METTL3-mediated m6A deposition onto nascent RNA following recruitment. At transcription termination regions, this nexus of actions promotes XRN2-mediated termination of RNAPII transcription. Disruption of any of these steps, including the loss of DDX21, METTL3, or their enzymatic activities, leads to defective termination that can induce DNA damage. Therefore, we propose that the R-loop-DDX21-METTL3 nexus forges the missing link for co-transcriptional modification of m6A, coordinating transcription termination and genome stability.
    Keywords:  DDX21; DNA damage; METTL3; R-loops; RNA m(6)A methylation; XRN2; co-transcriptional regulation; genome stability; transcription termination; transcription-replication collisions
    DOI:  https://doi.org/10.1016/j.molcel.2024.03.006
  13. Nucleic Acids Res. 2024 Mar 30. pii: gkae205. [Epub ahead of print]
    Defective transfer of parental histone decreases frequency of homologous recombination by increasing free histone pools in budding yeast.
    Srinivasu Karri, Yi Yang, Jiaqi Zhou, Quinn Dickinson, Jing Jia, Yuxin Huang, Zhiquan Wang, Haiyun Gan, Chuanhe Yu.
      Recycling of parental histones is an important step in epigenetic inheritance. During DNA replication, DNA polymerase epsilon subunit DPB3/DPB4 and DNA replication helicase subunit MCM2 are involved in the transfer of parental histones to the leading and lagging strands, respectively. Single Dpb3 deletion (dpb3Δ) or Mcm2 mutation (mcm2-3A), which each disrupts one parental histone transfer pathway, leads to the other's predominance. However, the biological impact of the two histone transfer pathways on chromatin structure and DNA repair remains elusive. In this study, we used budding yeast Saccharomyces cerevisiae to determine the genetic and epigenetic outcomes from disruption of parental histone H3-H4 tetramer transfer. We found that a dpb3Δ mcm2-3A double mutant did not exhibit the asymmetric parental histone patterns caused by a single dpb3Δ or mcm2-3A mutation, suggesting that the processes by which parental histones are transferred to the leading and lagging strands are independent. Surprisingly, the frequency of homologous recombination was significantly lower in dpb3Δ, mcm2-3A and dpb3Δ mcm2-3A mutants, likely due to the elevated levels of free histones detected in the mutant cells. Together, these findings indicate that proper transfer of parental histones during DNA replication is essential for maintaining chromatin structure and that lower homologous recombination activity due to parental histone transfer defects is detrimental to cells.
    DOI:  https://doi.org/10.1093/nar/gkae205
  14. Cancer Cell. 2024 Apr 02. pii: S1535-6108(24)00093-X. [Epub ahead of print]
    Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.
    Avishay Spitzer, Simon Gritsch, Masashi Nomura, Alexander Jucht, Jerome Fortin, Ramya Raviram, Hannah R Weisman, L Nicolas Gonzalez Castro, Nicholas Druck, Rony Chanoch-Myers, John J Y Lee, Ravindra Mylvaganam, Rachel Lee Servis, Jeremy Man Fung, Christine K Lee, Hiroaki Nagashima, Julie J Miller, Isabel Arrillaga-Romany, David N Louis, Hiroaki Wakimoto, Will Pisano, Patrick Y Wen, Tak W Mak, Marc Sanson, Mehdi Touat, Dan A Landau, Keith L Ligon, Daniel P Cahill, Mario L Suvà, Itay Tirosh.
      A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
    Keywords:  IDH1; differentiation therapy; glioma; ivosidenib; oligodendroglioma; single cell RNA-seq; vorasidenib
    DOI:  https://doi.org/10.1016/j.ccell.2024.03.008
  15. Dev Cell. 2024 Apr 01. pii: S1534-5807(24)00144-8. [Epub ahead of print]
    Iterative oxidation by TET1 is required for reprogramming of imprinting control regions and patterning of mouse sperm hypomethylated regions.
    Rexxi D Prasasya, Blake A Caldwell, Zhengfeng Liu, Songze Wu, N Adrian Leu, Johanna M Fowler, Steven A Cincotta, Diana J Laird, Rahul M Kohli, Marisa S Bartolomei.
      Ten-eleven translocation (TET) enzymes iteratively oxidize 5-methylcytosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during mammalian germline reprogramming remains unresolved due to the inability to decouple TET activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls oxidation at 5hmC (Tet1-V). Tet1 knockout and catalytic mutant primordial germ cells (PGCs) fail to erase methylation at select imprinting control regions and promoters of meiosis-associated genes, validating the requirement for the iterative oxidation of 5mC for complete germline reprogramming. TET1V and TET1HxD rescue most hypermethylation of Tet1-/- sperm, suggesting the role of TET1 beyond its oxidative capability. We additionally identify a broader class of hypermethylated regions in Tet1 mutant mouse sperm that depend on TET oxidation for reprogramming. Our study demonstrates the link between TET1-mediated germline reprogramming and sperm methylome patterning.
    Keywords:  DNA methylation; TET enzyme; epigenetic; germline reprogramming; imprinting; primordial germ cell establishment; reprogramming; sperm DNA methylation establishment; sperm methylome
    DOI:  https://doi.org/10.1016/j.devcel.2024.02.012
  16. EMBO J. 2024 Apr 02.
    Genome-scale chromatin binding dynamics of RNA Polymerase II general transcription machinery components.
    Kristyna Kupkova, Savera J Shetty, Elizabeth A Hoffman, Stefan Bekiranov, David T Auble.
      A great deal of work has revealed, in structural detail, the components of the preinitiation complex (PIC) machinery required for initiation of mRNA gene transcription by RNA polymerase II (Pol II). However, less-well understood are the in vivo PIC assembly pathways and their kinetics, an understanding of which is vital for determining how rates of in vivo RNA synthesis are established. We used competition ChIP in budding yeast to obtain genome-scale estimates of the residence times for five general transcription factors (GTFs): TBP, TFIIA, TFIIB, TFIIE and TFIIF. While many GTF-chromatin interactions were short-lived ( < 1 min), there were numerous interactions with residence times in the range of several minutes. Sets of genes with a shared function also shared similar patterns of GTF kinetic behavior. TFIIE, a GTF that enters the PIC late in the assembly process, had residence times correlated with RNA synthesis rates. The datasets and results reported here provide kinetic information for most of the Pol II-driven genes in this organism, offering a rich resource for exploring the mechanistic relationships between PIC assembly, gene regulation, and transcription.
    Keywords:  Competition ChIP; Kinetics; Preinitiation Complex; Synthesis Rates
    DOI:  https://doi.org/10.1038/s44318-024-00089-2
  17. Cell Rep. 2024 Apr 02. pii: S2211-1247(24)00372-3. [Epub ahead of print]43(4): 114044
    A senescence restriction point acting on chromatin integrates oncogenic signals.
    Stéphane Lopes-Paciencia, Véronique Bourdeau, Marie-Camille Rowell, Davoud Amirimehr, Jordan Guillon, Paloma Kalegari, Arnab Barua, Vincent Quoc-Huy Trinh, Feryel Azzi, Simon Turcotte, Adrian Serohijos, Gerardo Ferbeyre.
      We identify a senescence restriction point (SeRP) as a critical event for cells to commit to senescence. The SeRP integrates the intensity and duration of oncogenic stress, keeps a memory of previous stresses, and combines oncogenic signals acting on different pathways by modulating chromatin accessibility. Chromatin regions opened upon commitment to senescence are enriched in nucleolar-associated domains, which are gene-poor regions enriched in repeated sequences. Once committed to senescence, cells no longer depend on the initial stress signal and exhibit a characteristic transcriptome regulated by a transcription factor network that includes ETV4, RUNX1, OCT1, and MAFB. Consistent with a tumor suppressor role for this network, the levels of ETV4 and RUNX1 are very high in benign lesions of the pancreas but decrease dramatically in pancreatic ductal adenocarcinomas. The discovery of senescence commitment and its chromatin-linked regulation suggests potential strategies for reinstating tumor suppression in human cancers.
    Keywords:  CP: Cancer; ERK; ETV4; RUNX1; chromatin; commitment; oncogenic memory; pancreatic cancer; restriction point; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2024.114044
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