bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–11–05
nineteen papers selected by
Connor Rogerson, University of Cambridge
  1. scATAC-Ref: a reference of scATAC-seq with known cell labels in multiple species.
  2. Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation.
  3. Accessible high-throughput single-cell whole-genome sequencing with paired chromatin accessibility.
  4. A protocol for simultaneous high-sensitivity genotyping and chromatin accessibility profiling in single cells.
  5. E4F1 and ZNF148 are transcriptional activators of the -57A>C and wild-type TERT promoter.
  6. HHCDB: a database of human heterochromatin regions.
  7. GNet: An integrated context-aware neural framework for transcription factor binding signal at single nucleotide resolution prediction.
  8. eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk.
  9. Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity.
  10. Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity.
  11. Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia.
  12. In-organoid single-cell CRISPR screening reveals determinants of hepatocyte differentiation and maturation.
  13. TOR inactivation triggers heterochromatin formation in rDNA during glucose starvation.
  14. Replisome loading reduces chromatin motion independent of DNA synthesis.
  15. Sequence and epigenetic landscapes of active and silent nucleolus organizer regions in Arabidopsis.
  16. The lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males.
  17. The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts.
  18. Isoform-resolved transcriptome of the human preimplantation embryo.
  19. The chromatin source-sink hypothesis: a shared mode of chromatin-mediated regulations.
  1. Nucleic Acids Res. 2023 Oct 28. pii: gkad924. [Epub ahead of print]
    scATAC-Ref: a reference of scATAC-seq with known cell labels in multiple species.
    Feng-Cui Qian, Li-Wei Zhou, Yan-Bing Zhu, Yan-Yu Li, Zheng-Min Yu, Chen-Chen Feng, Qiao-Li Fang, Yu Zhao, Fu-Hong Cai, Qiu-Yu Wang, Hui-Fang Tang, Chun-Quan Li.
      Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.
    DOI:  https://doi.org/10.1093/nar/gkad924
  2. Nat Commun. 2023 Oct 30. 14(1): 6929
    Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation.
    Kirstin Meyer, Nicholas C Lammers, Lukasz J Bugaj, Hernan G Garcia, Orion D Weiner.
      YAP is a transcriptional regulator that controls pluripotency, cell fate, and proliferation. How cells ensure the selective activation of YAP effector genes is unknown. This knowledge is essential to rationally control cellular decision-making. Here we leverage optogenetics, live-imaging of transcription, and cell fate analysis to understand and control gene activation and cell behavior. We reveal that cells decode the steady-state concentrations and timing of YAP activation to control proliferation, cell fate, and expression of the pluripotency regulators Oct4 and Nanog. While oscillatory YAP inputs induce Oct4 expression and proliferation optimally at frequencies that mimic native dynamics, cellular differentiation requires persistently low YAP levels. We identify the molecular logic of the Oct4 dynamic decoder, which acts through an adaptive change sensor. Our work reveals how YAP levels and dynamics enable multiplexing of information transmission for the regulation of developmental decision-making and establishes a platform for the rational control of these behaviors.
    DOI:  https://doi.org/10.1038/s41467-023-42643-2
  3. Cell Rep Methods. 2023 Oct 26. pii: S2667-2375(23)00289-8. [Epub ahead of print] 100625
    Accessible high-throughput single-cell whole-genome sequencing with paired chromatin accessibility.
    Konstantin Queitsch, Travis W Moore, Brendan L O'Connell, Ruth V Nichols, John L Muschler, Dove Keith, Charles Lopez, Rosalie C Sears, Gordon B Mills, Galip Gürkan Yardımcı, Andrew C Adey.
      Single-cell whole-genome sequencing (scWGS) enables the assessment of genome-level molecular differences between individual cells with particular relevance to genetically diverse systems like solid tumors. The application of scWGS was limited due to a dearth of accessible platforms capable of producing high-throughput profiles. We present a technique that leverages nucleosome disruption methodologies with the widely adopted 10× Genomics ATAC-seq workflow to produce scWGS profiles for high-throughput copy-number analysis without new equipment or custom reagents. We further demonstrate the use of commercially available indexed transposase complexes from ScaleBio for sample multiplexing, reducing the per-sample preparation costs. Finally, we demonstrate that sequential indexed tagmentation with an intervening nucleosome disruption step allows for the generation of both ATAC and WGS data from the same cell, producing comparable data to the unimodal assays. By exclusively utilizing accessible commercial reagents, we anticipate that these scWGS and scWGS+ATAC methods can be broadly adopted by the research community.
    Keywords:  CP: Biotechnology; CP: Genetics; cancer biology; chromatin accessibility; copy-number alterations; single-cell genomics
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100625
  4. STAR Protoc. 2023 Oct 26. pii: S2666-1667(23)00608-1. [Epub ahead of print]4(4): 102641
    A protocol for simultaneous high-sensitivity genotyping and chromatin accessibility profiling in single cells.
    Sven Turkalj, Niels Asger Jakobsen, Angus Groom, Felix A Radtke, Paresh Vyas.
      Single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) resolves the heterogeneity of epigenetic states across cells but does not typically capture exonic mutations, which limits our knowledge of how somatic mutations alter chromatin landscapes. Here, we present a plate-based approach coupling high-sensitivity genotyping of genomic loci with high-content scATAC-seq libraries from the same single cells. We first describe steps for optimization of genotyping primers, followed by detailed guidance on the preparation of both scATAC-seq and single-cell genotyping libraries, fully automated on high-throughput liquid handling platforms. For complete details on the use and execution of this protocol, please refer to Turkalj, Jakobsen et al.1.
    Keywords:  Bioinformatics; Cancer; Genetics; Genomics; Molecular Biology; Sequence Analysis; Sequencing; Single Cell; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102641
  5. Genome Res. 2023 Nov 02. pii: gr.277724.123. [Epub ahead of print]
    E4F1 and ZNF148 are transcriptional activators of the -57A>C and wild-type TERT promoter.
    Boon Haow Chua, Nurkaiyisah Zaal Anuar, Laure Ferry, Cecilia Domrane, Anna Wittek, Vineeth Mukundan, Sudhakar Jha, Falk Butter, Daniel Geoffrey Tenen, Pierre-Antoine Defossez, Dennis Kappei.
      Point mutations within the TERT promoter are the most recurrent somatic noncoding mutations identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma, and bladder cancer. They are most abundant at -146C>T and -124C>T and rarer at -57A>C, with the latter originally described as a familial case, but subsequently shown also to occur somatically. All three mutations create de novo ETS (E-twenty-six specific) binding sites and result in activation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we employed a systematic proteomics screen to identify transcription factors preferentially binding to the -146C>T, -124C>T and -57A>C mutations. While we confirmed binding of multiple ETS factors to the mutant -146C>T and -124C>T sequences, we identified E4F1 as an -57A>C-specific binder and ZNF148 as a TERT wild-type promoter binder that showed reduced interaction with the -124C>T allele. Both proteins are activating transcription factors that bind specifically to the -57A>C and wild-type (at position 124) TERT promoter sequence in corresponding cell lines and upregulate TERT transcription and telomerase activity. Our work describes new regulators of TERT gene expression with possible roles in cancer.
    DOI:  https://doi.org/10.1101/gr.277724.123
  6. Nucleic Acids Res. 2023 Oct 28. pii: gkad954. [Epub ahead of print]
    HHCDB: a database of human heterochromatin regions.
    Hongli Wang, Mu Su, Jie Xing, Jie Zhou, Jinzhang Wang, Long Chen, Haomin Dong, Wenhui Xue, Yubo Liu, Qiong Wu, Yan Zhang.
      Heterochromatin plays essential roles in eukaryotic genomes, such as regulating genes, maintaining genome integrity and silencing repetitive DNA elements. Identifying genome-wide heterochromatin regions is crucial for studying transcriptional regulation. We propose the Human Heterochromatin Chromatin Database (HHCDB) for archiving heterochromatin regions defined by specific or combined histone modifications (H3K27me3, H3K9me2, H3K9me3) according to a unified pipeline. 42 839 743 heterochromatin regions were identified from 578 samples derived from 241 cell-types/cell lines and 92 tissue types. Genomic information is provided in HHCDB, including chromatin location, gene structure, transcripts, distance from transcription start site, neighboring genes, CpG islands, transposable elements, 3D genomic structure and functional annotations. Furthermore, transcriptome data from 73 single cells were analyzed and integrated to explore cell type-specific heterochromatin-related genes. HHCDB affords rich visualization through the UCSC Genome Browser and our self-developed tools. We have also developed a specialized online analysis platform to mine differential heterochromatin regions in cancers. We performed several analyses to explore the function of cancer-specific heterochromatin-related genes, including clinical feature analysis, immune cell infiltration analysis and the construction of drug-target networks. HHCDB is a valuable resource for studying epigenetic regulation, 3D genomics and heterochromatin regulation in development and disease. HHCDB is freely accessible at http://hhcdb.edbc.org/.
    DOI:  https://doi.org/10.1093/nar/gkad954
  7. Math Biosci Eng. 2023 Jul 31. 20(9): 15809-15829
    GNet: An integrated context-aware neural framework for transcription factor binding signal at single nucleotide resolution prediction.
    Jujuan Zhuang, Kexin Feng, Xinyang Teng, Cangzhi Jia.
      Transcription factors (TFs) are important factors that regulate gene expression. Revealing the mechanism affecting the binding specificity of TFs is the key to understanding gene regulation. Most of the previous studies focus on TF-DNA binding sites at the sequence level, and they seldom utilize the contextual features of DNA sequences. In this paper, we develop an integrated spatiotemporal context-aware neural network framework, named GNet, for predicting TF-DNA binding signal at single nucleotide resolution by achieving three tasks: single nucleotide resolution signal prediction, identification of binding regions at the sequence level, and TF-DNA binding motif prediction. GNet extracts implicit spatial contextual information with a gated highway neural mechanism, which captures large context multi-level patterns using linear shortcut connections, and the idea of it permeates the encoder and decoder parts of GNet. The improved dual external attention mechanism, which learns implicit relationships both within and among samples, and improves the performance of the model. Experimental results on 53 human TF ChIP-seq datasets and 6 chromatin accessibility ATAC-seq datasets shows that GNet outperforms the state-of-the-art methods in the three tasks, and the results of cross-species studies on 15 human and 18 mouse TF datasets of the corresponding TF families indicate that GNet also shows the best performance in cross-species prediction over the competitive methods.
    Keywords:   encoder-decoder architecture ; external attention mechanism ; gated highway neural network ; transcription factor binding site
    DOI:  https://doi.org/10.3934/mbe.2023704
  8. Nat Commun. 2023 Oct 30. 14(1): 6928
    eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk.
    iPSCORE Consortium
      The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
    DOI:  https://doi.org/10.1038/s41467-023-42560-4
  9. Genes Dev. 2023 Nov 01.
    Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity.
    Mrinmoy Pal, Luis Altamirano-Pacheco, Tamas Schauer, Maria-Elena Torres-Padilla.
      Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis, including zygotic genome activation (ZGA) during maternal-to-zygotic transition, influence such remodeling remains unknown. Here, we have investigated the establishment of nuclear architecture, focusing on the remodeling of lamina-associated domains (LADs) during this transition. We report that LADs reorganize gradually in two-cell embryos and that blocking ZGA leads to major changes in nuclear organization, including altered chromatin and genomic features of LADs and redistribution of H3K4me3 toward the nuclear lamina. Our data indicate that the rearrangement of LADs is an integral component of the maternal-to-zygotic transition and that transcription contributes to shaping nuclear organization at the beginning of mammalian development.
    Keywords:  ZGA; embryonic development; lamina-associated domain; nuclear organization
    DOI:  https://doi.org/10.1101/gad.350799.123
  10. EMBO Mol Med. 2023 Oct 30. e17737
    Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity.
    Stefan Prekovic, Theofilos Chalkiadakis, Merel Roest, Daniel Roden, Catrin Lutz, Karianne Schuurman, Mark Opdam, Liesbeth Hoekman, Nina Abbott, Tanja Tesselaar, Maliha Wajahat, Amy R Dwyer, Isabel Mayayo-Peralta, Gabriela Gomez, Maarten Altelaar, Roderick Beijersbergen, Balázs Győrffy, Leonie Young, Sabine Linn, Jos Jonkers, Wayne Tilley, Theresa Hickey, Damir Vareslija, Alexander Swarbrick, Wilbert Zwart.
      Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico-designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER-positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer-driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER-positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER-positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.
    Keywords:  ZBTB16; breast cancer; glucocorticoids; luminal breast cancer subtypes; nuclear receptors
    DOI:  https://doi.org/10.15252/emmm.202317737
  11. Blood. 2023 Nov 03. pii: blood.2023020857. [Epub ahead of print]
    Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia.
    Kazunari Aoki, Mizuki Hyuga, Yusuke Tarumoto, Gohei Nishibuchi, Atsushi Ueda, Yotaro Ochi, Seiichi Sugino, Takashi Mikami, Hirokazu Kobushi, Itaru Kato, Koshi Akahane, Takeshi Inukai, Akifumi Takaori-Kondo, Junko Takita, Seishi Ogawa, Kosuke Yusa.
      Acute leukemia cells require bone marrow microenvironments, termed niches, which provide leukemic cells with niche factors that are essential for leukemic cell survival and/or proliferation. However, it remains unclear how the dynamics of the leukemic cell-niche interaction are regulated. Using a genome-wide CRISPR screen, we discovered that canonical BRG1/BRM-associated factor (cBAF), a variant of the switch/sucrose non-fermenting chromatin remodeling complex, regulates migratory response of human T-cell acute lymphoblastic leukemia (T-ALL) cells to a niche factor CXCL12. Mechanistically, cBAF maintains chromatin accessibility and allows RUNX1 to bind to CXCR4 enhancer regions. cBAF inhibition evicts RUNX1 from the genome, resulting in CXCR4 downregulation and impaired migration activity. In addition, cBAF maintains chromatin accessibility preferentially at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CDK6; therefore, cBAF inhibition negatively impacts cell proliferation and profoundly induces apoptosis. This anticancer effect was also confirmed using T-ALL xenograft models, suggesting cBAF as a promising therapeutic target. Thus, we provide novel evidence that cBAF regulates the RUNX1-driven leukemic program and governs migration activity toward CXCL12 and cell-autonomous growth in human T-ALL.
    DOI:  https://doi.org/10.1182/blood.2023020857
  12. Genome Biol. 2023 Oct 31. 24(1): 251
    In-organoid single-cell CRISPR screening reveals determinants of hepatocyte differentiation and maturation.
    Junbo Liang, Jinsong Wei, Jun Cao, Jun Qian, Ran Gao, Xiaoyu Li, Dingding Wang, Yani Gu, Lei Dong, Jia Yu, Bing Zhao, Xiaoyue Wang.
       BACKGROUND: Harnessing hepatocytes for basic research and regenerative medicine demands a complete understanding of the genetic determinants underlying hepatocyte differentiation and maturation. Single-cell CRISPR screens in organoids could link genetic perturbations with parallel transcriptomic readout in single cells, providing a powerful method to delineate roles of cell fate regulators. However, a big challenge for identifying key regulators during data analysis is the low expression levels of transcription factors (TFs), which are difficult to accurately estimate due to noise and dropouts in single-cell sequencing. Also, it is often the changes in TF activities in the transcriptional cascade rather than the expression levels of TFs that are relevant to the cell fate transition.
    RESULTS: Here, we develop Organoid-based Single-cell CRISPR screening Analyzed with Regulons (OSCAR), a framework using regulon activities as readouts to dissect gene knockout effects in organoids. In adult-stem-cell-derived liver organoids, we map transcriptomes in 80,576 cells upon 246 perturbations associated with transcriptional regulation of hepatocyte formation. Using OSCAR, we identify known and novel positive and negative regulators, among which Fos and Ubr5 are the top-ranked ones. Further single-gene loss-of-function assays demonstrate that Fos depletion in mouse and human liver organoids promote hepatocyte differentiation by specific upregulation of liver metabolic genes and pathways, and conditional knockout of Ubr5 in mouse liver delays hepatocyte maturation.
    CONCLUSIONS: Altogether, we provide a framework to explore lineage specifiers in a rapid and systematic manner, and identify hepatocyte determinators with potential clinical applications.
    Keywords:  Hepatocyte differentiation and maturation; Organoid; Regulon; Single-cell CRISPR screen
    DOI:  https://doi.org/10.1186/s13059-023-03084-8
  13. Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01332-3. [Epub ahead of print] 113320
    TOR inactivation triggers heterochromatin formation in rDNA during glucose starvation.
    Hayato Hirai, Yuki Sen, Miki Tamura, Kunihiro Ohta.
      In response to environmental cues, such as nutrient starvation, living organisms modulate gene expression through mechanisms involving histone modifications. Specifically, nutrient depletion inactivates the TOR (target of rapamycin) pathway, leading to reduced expression of ribosomal genes. While these regulatory mechanisms are well elucidated in budding yeast Saccharomyces cerevisiae, their conservation across diverse organisms remains unclear. In this study, we demonstrate that fission yeast Schizosaccharomyces pombe cells repress ribosomal gene transcription through a different mechanism. TORC1, which accumulates in the rDNA region, dissociates upon starvation, resulting in enhanced methylation of H3K9 and heterochromatin formation, facilitated by dissociation of the stress-responsive transcription factor Atf1 and accumulation of the histone chaperone FACT. We propose that this mechanism might be adapted in mammals that possess Suv39H1 and HP1, which are absent in budding yeast.
    Keywords:  ATF/CREB; CP: Molecular biology; TOR pathway; fission yeast; heterochromatin; ribosome; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2023.113320
  14. Elife. 2023 Oct 31. pii: RP87572. [Epub ahead of print]12
    Replisome loading reduces chromatin motion independent of DNA synthesis.
    Maruthi Kumar Pabba, Christian Ritter, Vadim O Chagin, Janis Meyer, Kerem Celikay, Jeffrey H Stear, Dinah Loerke, Ksenia Kolobynina, Paulina Prorok, Alice Kristin Schmid, Heinrich Leonhardt, Karl Rohr, M Cristina Cardoso.
      Chromatin has been shown to undergo diffusional motion, which is affected during gene transcription by RNA polymerase activity. However, the relationship between chromatin mobility and other genomic processes remains unclear. Hence, we set out to label the DNA directly in a sequence unbiased manner and followed labeled chromatin dynamics in interphase human cells expressing GFP-tagged proliferating cell nuclear antigen (PCNA), a cell cycle marker and core component of the DNA replication machinery. We detected decreased chromatin mobility during the S-phase compared to G1 and G2 phases in tumor as well as normal diploid cells using automated particle tracking. To gain insight into the dynamical organization of the genome during DNA replication, we determined labeled chromatin domain sizes and analyzed their motion in replicating cells. By correlating chromatin mobility proximal to the active sites of DNA synthesis, we showed that chromatin motion was locally constrained at the sites of DNA replication. Furthermore, inhibiting DNA synthesis led to increased loading of DNA polymerases. This was accompanied by accumulation of the single-stranded DNA binding protein on the chromatin and activation of DNA helicases further restricting local chromatin motion. We, therefore, propose that it is the loading of replisomes but not their catalytic activity that reduces the dynamics of replicating chromatin segments in the S-phase as well as their accessibility and probability of interactions with other genomic regions.
    Keywords:  DNA labeling; DNA replication; aphidicolin; cell biology; cell cycle; chromatin tracking; diffusion; human
    DOI:  https://doi.org/10.7554/eLife.87572
  15. Sci Adv. 2023 11 03. 9(44): eadj4509
    Sequence and epigenetic landscapes of active and silent nucleolus organizer regions in Arabidopsis.
    Dalen Fultz, Anastasia McKinlay, Ramya Enganti, Craig S Pikaard.
      Arabidopsis thaliana has two ribosomal RNA (rRNA) gene loci, nucleolus organizer regions NOR2 and NOR4, whose complete sequences are missing in current genome assemblies. Ultralong DNA sequences assembled using an unconventional approach yielded ~5.5- and 3.9-Mbp sequences for NOR2 and NOR4 in the reference strain, Col-0. The distinct rRNA gene subtype compositions of the NORs enabled the positional mapping of their active and inactive regions, using RNA sequencing to identify subtype-specific transcripts and DNA sequencing to identify subtypes associated with flow-sorted nucleoli. Comparisons of wild-type and silencing-defective plants revealed that most rRNA gene activity occurs in the central region of NOR4, whereas most, but not all, genes of NOR2 are epigenetically silenced. Intervals of low CG and CHG methylation overlap regions where gene activity and gene subtype homogenization are high. Collectively, the data reveal the genetic and epigenetic landscapes underlying nucleolar dominance (differential NOR activity) and implicate transcription as a driver of rRNA gene concerted evolution.
    DOI:  https://doi.org/10.1126/sciadv.adj4509
  16. Nat Commun. 2023 Nov 02. 14(1): 7024
    The lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males.
    Sandra Rogala, Tamer Ali, Maria-Theodora Melissari, Sandra Währisch, Peggy Schuster, Alexandre Sarre, Rebeca Cordellini Emídio, Thomas Boettger, Eva-Maria Rogg, Jaskiran Kaur, Jaya Krishnan, Gabrijela Dumbović, Stefanie Dimmeler, Samir Ounzain, Thierry Pedrazzini, Bernhard G Herrmann, Phillip Grote.
      After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are taking part in fine-tuning such gene programs. We describe and characterize the cardiomyocyte specific lncRNA Sweetheart RNA (Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding gene Nkx2-5. We show that Swhtr is dispensable for normal heart development and function but becomes essential for the tissue adaptation process after myocardial infarction in murine males. Re-expressing Swhtr from an exogenous locus rescues the Swhtr null phenotype. Genes that depend on Swhtr after cardiac stress are significantly occupied and therefore most likely regulated by NKX2-5. The Swhtr transcript interacts with NKX2-5 and disperses upon hypoxic stress in cardiomyocytes, indicating an auxiliary role of Swhtr for NKX2-5 function in tissue adaptation after myocardial injury.
    DOI:  https://doi.org/10.1038/s41467-023-42760-y
  17. Nat Commun. 2023 10 28. 14(1): 6890
    The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts.
    Aleix Bayona-Feliu, Emilia Herrera-Moyano, Nibal Badra-Fajardo, Iván Galván-Femenía, María Eugenia Soler-Oliva, Andrés Aguilera.
      Genome instability is a feature of cancer cells, transcription being an important source of DNA damage. This is in large part associated with R-loops, which hamper replication, especially at head-on transcription-replication conflicts (TRCs). Here we show that TRCs trigger a DNA Damage Response (DDR) involving the chromatin network to prevent genome instability. Depletion of the key chromatin factors INO80, SMARCA5 and MTA2 results in TRCs, fork stalling and R-loop-mediated DNA damage which mostly accumulates at S/G2, while histone H3 Ser10 phosphorylation, a mark of chromatin compaction, is enriched at TRCs. Strikingly, TRC regions show increased mutagenesis in cancer cells with signatures of homologous recombination deficiency, transcription-coupled nucleotide excision repair (TC-NER) and of the AID/APOBEC cytidine deaminases, being predominant at head-on collisions. Thus, our results support that the chromatin network prevents R-loops and TRCs from genomic instability and mutagenic signatures frequently associated with cancer.
    DOI:  https://doi.org/10.1038/s41467-023-42653-0
  18. Nat Commun. 2023 Oct 30. 14(1): 6902
    Isoform-resolved transcriptome of the human preimplantation embryo.
    Denis Torre, Nancy J Francoeur, Yael Kalma, Ilana Gross Carmel, Betsaida S Melo, Gintaras Deikus, Kimaada Allette, Ron Flohr, Maya Fridrikh, Konstantinos Vlachos, Kent Madrid, Hardik Shah, Ying-Chih Wang, Shwetha H Sridhar, Melissa L Smith, Efrat Eliyahu, Foad Azem, Hadar Amir, Yoav Mayshar, Ivan Marazzi, Ernesto Guccione, Eric Schadt, Dalit Ben-Yosef, Robert Sebra.
      Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development.
    DOI:  https://doi.org/10.1038/s41467-023-42558-y
  19. Development. 2023 Nov 01. pii: dev201989. [Epub ahead of print]150(21):
    The chromatin source-sink hypothesis: a shared mode of chromatin-mediated regulations.
    Patrick J Murphy, Frédéric Berger.
      We propose that several chromatin-mediated regulatory processes are dominated by source-sink relationships in which factors operate as 'sources' to produce or provide a resource and compete with each other to occupy separate 'sinks'. In this model, large portions of genomic DNA operate as 'sinks', which are filled by 'sources', such as available histone variants, covalent modifications to histones, the readers of these modifications and non-coding RNAs. Competing occupation for the sinks by different sources leads to distinct states of genomic equilibrium in differentiated cells. During dynamic developmental events, such as sexual reproduction, we propose that dramatic and rapid reconfiguration of source-sink relationships modifies chromatin states. We envision that re-routing of sources could occur by altering the dimensions of the sink, by reconfiguration of existing sink occupation or by varying the size of the source, providing a central mechanism to explain a plethora of epigenetic phenomena, which contribute to phenotypic variegation, zygotic genome activation and nucleolar dominance.
    Keywords:  Chromatin; Epigenetics; Evolution; Transposons; Zygotic activation
    DOI:  https://doi.org/10.1242/dev.201989
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