bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024‒01‒28
seventeen papers selected by
Connor Rogerson, University of Cambridge
  1. DNA-guided transcription factor cooperativity shapes face and limb mesenchyme.
  2. Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα.
  3. SATB2 organizes the 3D genome architecture of cognition in cortical neurons.
  4. Massively parallel disruption of enhancers active in human neural stem cells.
  5. Genomic overview of INA-induced NPR1 targeting and transcriptional cascades in Arabidopsis.
  6. Intrinsic protein disorder is insufficient to drive subnuclear clustering in embryonic transcription factors.
  7. Uncovering the roles of DNA hemi-methylation in transcriptional regulation using MspJI-assisted hemi-methylation sequencing.
  8. Chromatin phase separated nanoregions explored by polymer cross-linker models and reconstructed from single particle trajectories.
  9. A mucus production programme promotes classical pancreatic ductal adenocarcinoma.
  10. Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis.
  11. The nucleolar shell provides anchoring sites for DNA untwisting.
  12. HSP70 binds to specific non-coding RNA and regulates human RNA polymerase III.
  13. Intrinsically Disordered Regions in the Transcription Factor MYC:MAX Modulate DNA Binding via Intramolecular Interactions.
  14. Cis-regulatory modes of Ultrabithorax inactivation in butterfly forewings.
  15. The UBP5 histone H2A deubiquitinase counteracts PRCs-mediated repression to regulate Arabidopsis development.
  16. Reconstructing DNA methylation maps of ancient populations.
  17. A genome-wide comprehensive analysis of nucleosome positioning in yeast.
  1. Cell. 2024 Jan 17. pii: S0092-8674(23)01438-1. [Epub ahead of print]
    DNA-guided transcription factor cooperativity shapes face and limb mesenchyme.
    Seungsoo Kim, Ekaterina Morgunova, Sahin Naqvi, Seppe Goovaerts, Maram Bader, Mervenaz Koska, Alexander Popov, Christy Luong, Angela Pogson, Tomek Swigut, Peter Claes, Jussi Taipale, Joanna Wysocka.
      Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest that it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how "Coordinator," a long DNA motif composed of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines the regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, whereas HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in the shared regulation of genes involved in cell-type and positional identities and ultimately shapes facial morphology and evolution.
    Keywords:  ALX factors; Coordinator; TWIST1; bHLH; cooperativity; face; homeodomain; limb; mesenchyme; neural crest; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2023.12.032
  2. Nat Struct Mol Biol. 2024 Jan 24.
    Structural mechanism of synergistic targeting of the CX3CR1 nucleosome by PU.1 and C/EBPα.
    Tengfei Lian, Ruifang Guan, Bing-Rui Zhou, Yawen Bai.
      Pioneer transcription factors are vital for cell fate changes. PU.1 and C/EBPα work together to regulate hematopoietic stem cell differentiation. However, how they recognize in vivo nucleosomal DNA targets remains elusive. Here we report the structures of the nucleosome containing the mouse genomic CX3CR1 enhancer DNA and its complexes with PU.1 alone and with both PU.1 and the C/EBPα DNA binding domain. Our structures reveal that PU.1 binds the DNA motif at the exit linker, shifting 17 bp of DNA into the core region through interactions with H2A, unwrapping ~20 bp of nucleosomal DNA. C/EBPα binding, aided by PU.1's repositioning, unwraps ~25 bp of entry DNA. The PU.1 Q218H mutation, linked to acute myeloid leukemia, disrupts PU.1-H2A interactions. PU.1 and C/EBPα jointly displace linker histone H1 and open the H1-condensed nucleosome array. Our study unveils how two pioneer factors can work cooperatively to open closed chromatin by altering DNA positioning in the nucleosome.
    DOI:  https://doi.org/10.1038/s41594-023-01189-z
  3. Mol Cell. 2024 Jan 17. pii: S1097-2765(23)01070-5. [Epub ahead of print]
    SATB2 organizes the 3D genome architecture of cognition in cortical neurons.
    Nico Wahl, Sergio Espeso-Gil, Paola Chietera, Amelie Nagel, Aodán Laighneach, Derek W Morris, Prashanth Rajarajan, Schahram Akbarian, Georg Dechant, Galina Apostolova.
      The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (3D) epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal-activity-regulated genes, thus influencing their expression. It also alters A/B compartments, topologically associating domains, and frequently interacting regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with a SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence, and schizophrenia. Our data establish SATB2 as a cell-type-specific 3D genome modulator, which operates both independently and in cooperation with CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.
    Keywords:  3D genome; SATB2; chromatin accessibility; chromatin interactions; cognition; cortical neuron; epigenetics; neuronal genes; neuropsychiatric risk
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.024
  4. Cell Rep. 2024 Jan 23. pii: S2211-1247(24)00021-4. [Epub ahead of print]43(2): 113693
    Massively parallel disruption of enhancers active in human neural stem cells.
    Evan Geller, Mark A Noble, Matheo Morales, Jake Gockley, Deena Emera, Severin Uebbing, Justin L Cotney, James P Noonan.
      Changes in gene regulation have been linked to the expansion of the human cerebral cortex and to neurodevelopmental disorders, potentially by altering neural progenitor proliferation. However, the effects of genetic variation within regulatory elements on neural progenitors remain obscure. We use sgRNA-Cas9 screens in human neural stem cells (hNSCs) to disrupt 10,674 genes and 26,385 conserved regions in 2,227 enhancers active in the developing human cortex and determine effects on proliferation. Genes with proliferation phenotypes are associated with neurodevelopmental disorders and show biased expression in specific fetal human brain neural progenitor populations. Although enhancer disruptions overall have weaker effects than gene disruptions, we identify enhancer disruptions that severely alter hNSC self-renewal. Disruptions in human accelerated regions, implicated in human brain evolution, also alter proliferation. Integrating proliferation phenotypes with chromatin interactions reveals regulatory relationships between enhancers and their target genes contributing to neurogenesis and potentially to human cortical evolution.
    Keywords:  CP: Genomics; CP: Neuroscience; enhancers; gene regulation; human accelerated regions; human neural stem cells; neurodevelopment; neurodevelopmental disorders
    DOI:  https://doi.org/10.1016/j.celrep.2024.113693
  5. Nucleic Acids Res. 2024 Jan 23. pii: gkae019. [Epub ahead of print]
    Genomic overview of INA-induced NPR1 targeting and transcriptional cascades in Arabidopsis.
    Se-Hun Yun, Irfan Ullah Khan, Bosl Noh, Yoo-Sun Noh.
      The phytohormone salicylic acid (SA) triggers transcriptional reprogramming that leads to SA-induced immunity in plants. NPR1 is an SA receptor and master transcriptional regulator in SA-triggered transcriptional reprogramming. Despite the indispensable role of NPR1, genome-wide direct targets of NPR1 specific to SA signaling have not been identified. Here, we report INA (functional SA analog)-specific genome-wide targets of Arabidopsis NPR1 in plants expressing GFP-fused NPR1 under its native promoter. Analyses of NPR1-dependently expressed direct NPR1 targets revealed that NPR1 primarily activates genes encoding transcription factors upon INA treatment, triggering transcriptional cascades required for INA-induced transcriptional reprogramming and immunity. We identified genome-wide targets of a histone acetyltransferase, HAC1, including hundreds of co-targets shared with NPR1, and showed that NPR1 and HAC1 regulate INA-induced histone acetylation and expression of a subset of the co-targets. Genomic NPR1 targeting was principally mediated by TGACG-motif binding protein (TGA) transcription factors. Furthermore, a group of NPR1 targets mostly encoding transcriptional regulators was already bound to NPR1 in the basal state and showed more rapid and robust induction than other NPR1 targets upon SA signaling. Thus, our study unveils genome-wide NPR1 targeting, its role in transcriptional reprogramming, and the cooperativity between NPR1, HAC1, and TGAs in INA-induced immunity.
    DOI:  https://doi.org/10.1093/nar/gkae019
  6. Elife. 2024 Jan 26. pii: RP88221. [Epub ahead of print]12
    Intrinsic protein disorder is insufficient to drive subnuclear clustering in embryonic transcription factors.
    Colleen E Hannon, Michael B Eisen.
      Modern microscopy has revealed that core nuclear functions, including transcription, replication, and heterochromatin formation, occur in spatially restricted clusters. Previous work from our lab has shown that subnuclear high-concentration clusters of transcription factors may play a role in regulating RNA synthesis in the early Drosophila embryo. A nearly ubiquitous feature of eukaryotic transcription factors is that they contain intrinsically disordered regions (IDRs) that often arise from low complexity amino acid sequences within the protein. It has been proposed that IDRs within transcription factors drive co-localization of transcriptional machinery and target genes into high-concentration clusters within nuclei. Here, we test that hypothesis directly, by conducting a broad survey of the subnuclear localization of IDRs derived from transcription factors. Using a novel algorithm to identify IDRs in the Drosophila proteome, we generated a library of IDRs from transcription factors expressed in the early Drosophila embryo. We used this library to perform a high-throughput imaging screen in Drosophila Schneider-2 (S2) cells. We found that while subnuclear clustering does not occur when the majority of IDRs are expressed alone, it is frequently seen in full-length transcription factors. These results are consistent in live Drosophila embryos, suggesting that IDRs are insufficient to drive the subnuclear clustering behavior of transcription factors. Furthermore, the clustering of transcription factors in living embryos was unaffected by the deletion of IDR sequences. Our results demonstrate that IDRs are unlikely to be the primary molecular drivers of the clustering observed during transcription, suggesting a more complex and nuanced role for these disordered protein sequences.
    Keywords:  D. melanogaster; chromosomes; confocal microscopy; gene expression; protein disorder; protein structure prediction; transcription factors
    DOI:  https://doi.org/10.7554/eLife.88221
  7. Nucleic Acids Res. 2024 Jan 23. pii: gkae023. [Epub ahead of print]
    Uncovering the roles of DNA hemi-methylation in transcriptional regulation using MspJI-assisted hemi-methylation sequencing.
    Xiong Xiong, Hengye Chen, Qifan Zhang, Yangying Liu, Chenhuan Xu.
      Hemi-methylated cytosine dyads widely occur on mammalian genomic DNA, and can be stably inherited across cell divisions, serving as potential epigenetic marks. Previous identification of hemi-methylation relied on harsh bisulfite treatment, leading to extensive DNA degradation and loss of methylation information. Here we introduce Mhemi-seq, a bisulfite-free strategy, to efficiently resolve methylation status of cytosine dyads into unmethylation, strand-specific hemi-methylation, or full-methylation. Mhemi-seq reproduces methylomes from bisulfite-based sequencing (BS-seq & hpBS-seq), including the asymmetric hemi-methylation enrichment flanking CTCF motifs. By avoiding base conversion, Mhemi-seq resolves allele-specific methylation and associated imprinted gene expression more efficiently than BS-seq. Furthermore, we reveal an inhibitory role of hemi-methylation in gene expression and transcription factor (TF)-DNA binding, and some displays a similar extent of inhibition as full-methylation. Finally, we uncover new hemi-methylation patterns within Alu retrotransposon elements. Collectively, Mhemi-seq can accelerate the identification of DNA hemi-methylation and facilitate its integration into the chromatin environment for future studies.
    DOI:  https://doi.org/10.1093/nar/gkae023
  8. PLoS Comput Biol. 2024 Jan 24. 20(1): e1011794
    Chromatin phase separated nanoregions explored by polymer cross-linker models and reconstructed from single particle trajectories.
    Andrea Papale, David Holcman.
      Phase separated domains (PSDs) are ubiquitous in cell biology, representing nanoregions of high molecular concentration. PSDs appear at diverse cellular domains, such as neuronal synapses but also in eukaryotic cell nucleus, limiting the access of transcription factors and thus preventing gene expression. We develop a generalized cross-linker polymer model, to study PSDs: we show that increasing the number of cross-linkers induces a polymer condensation, preventing access of diffusing molecules. To investigate how the PSDs restrict the motion of diffusing molecules, we compute the mean residence and first escaping times. Finally, we develop a method based on mean-square-displacement of single particle trajectories to reconstruct the properties of PSDs from the continuum range of anomalous exponents. We also show here that PSD generated by polymers do not induces a long-range attracting field (potential well), in contrast with nanodomains at neuronal synapses. To conclude, PSDs can result from condensed chromatin organization, where the number of cross-linkers controls molecular access.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011794
  9. Gut. 2024 Jan 23. pii: gutjnl-2023-329839. [Epub ahead of print]
    A mucus production programme promotes classical pancreatic ductal adenocarcinoma.
    Claudia Tonelli, Georgi N Yordanov, Yuan Hao, Astrid Deschênes, Juliene Hinds, Pascal Belleau, Olaf Klingbeil, Erin Brosnan, Abhishek Doshi, Youngkyu Park, Ralph H Hruban, Christopher R Vakoc, Alexander Dobin, Jonathan Preall, David A Tuveson.
      OBJECTIVE: The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators.DESIGN: We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models.
    RESULTS: Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA - the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation in vivo. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and ERN2/IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation.
    CONCLUSIONS: Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.
    Keywords:  MUCUS; PANCREATIC CANCER; PRE-MALIGNANCY - GI TRACT
    DOI:  https://doi.org/10.1136/gutjnl-2023-329839
  10. Cell Rep. 2024 Jan 23. pii: S2211-1247(24)00031-7. [Epub ahead of print]43(2): 113703
    Spatiotemporal role of SETD2-H3K36me3 in murine pancreatic organogenesis.
    Ping Lu, Junyi Xu, Xuqing Shen, Jiajun Sun, Mingzhu Liu, Ningning Niu, Qidi Wang, Jing Xue.
      Pancreas development is tightly controlled by multilayer mechanisms. Despite years of effort, large gaps remain in understanding how histone modifications coordinate pancreas development. SETD2, a predominant histone methyltransferase of H3K36me3, plays a key role in embryonic stem cell differentiation, whose role in organogenesis remains elusive. Here, by combination of cleavage under targets and tagmentation (CUT&Tag), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and bulk RNA sequencing, we show a dramatic increase in the H3K36me3 level from the secondary transition phase and decipher the related transcriptional alteration. Using single-cell RNA sequencing, we define that pancreatic deletion of Setd2 results in abnormalities in both exocrine and endocrine lineages: hyperproliferative tip progenitor cells lead to abnormal differentiation; Ngn3+ endocrine progenitors decline due to the downregulation of Nkx2.2, leading to insufficient endocrine development. Thus, these data identify SETD2 as a crucial player in embryonic pancreas development, providing a clue to understanding the dysregulation of histone modifications in pancreatic disorders.
    Keywords:  CP: Developmental biology; H3K36me3; Setd2; epigenetics; histone modification; pancreas development; second transition
    DOI:  https://doi.org/10.1016/j.celrep.2024.113703
  11. Commun Biol. 2024 Jan 23. 7(1): 83
    The nucleolar shell provides anchoring sites for DNA untwisting.
    Jumpei Fukute, Koichiro Maki, Taiji Adachi.
      DNA underwinding (untwisting) is a crucial step in transcriptional activation. DNA underwinding occurs between the site where torque is generated by RNA polymerase (RNAP) and the site where the axial rotation of DNA is constrained. However, what constrains DNA axial rotation in the nucleus is yet unknown. Here, we show that the anchorage to the nuclear protein condensates constrains DNA axial rotation for DNA underwinding in the nucleolus. In situ super-resolution imaging of underwound DNA reveal that underwound DNA accumulates in the nucleolus, a nuclear condensate with a core-shell structure. Specifically, underwound DNA is distributed in the nucleolar core owing to RNA polymerase I (RNAPI) activities. Furthermore, underwound DNA in the core decreases when nucleolar shell components are prevented from binding to their recognition structure, G-quadruplex (G4). Taken together, these results suggest that the nucleolar shell provides anchoring sites that constrain DNA axial rotation for RNAPI-driven DNA underwinding in the core. Our findings will contribute to understanding how nuclear protein condensates make up constraints for the site-specific regulation of DNA underwinding and transcription.
    DOI:  https://doi.org/10.1038/s42003-023-05750-w
  12. Mol Cell. 2024 Jan 19. pii: S1097-2765(24)00002-9. [Epub ahead of print]
    HSP70 binds to specific non-coding RNA and regulates human RNA polymerase III.
    Sergio Leone, Avinash Srivastava, Andrés Herrero-Ruiz, Barbara Hummel, Lena Tittel, Roberto Campalastri, Fernando Aprile-Garcia, Jun Hao Tan, Prashant Rawat, Patrik Andersson, Anne E Willis, Ritwick Sawarkar.
      Molecular chaperones are critical for protein homeostasis and are implicated in several human pathologies such as neurodegeneration and cancer. While the binding of chaperones to nascent and misfolded proteins has been studied in great detail, the direct interaction between chaperones and RNA has not been systematically investigated. Here, we provide the evidence for widespread interaction between chaperones and RNA in human cells. We show that the major chaperone heat shock protein 70 (HSP70) binds to non-coding RNA transcribed by RNA polymerase III (RNA Pol III) such as tRNA and 5S rRNA. Global chromatin profiling revealed that HSP70 binds genomic sites of transcription by RNA Pol III. Detailed biochemical analyses showed that HSP70 alleviates the inhibitory effect of cognate tRNA transcript on tRNA gene transcription. Thus, our study uncovers an unexpected role of HSP70-RNA interaction in the biogenesis of a specific class of non-coding RNA with wider implications in cancer therapeutics.
    Keywords:  HSP70; RNA polymerase III; RNA-binding proteome; RNA-protein interaction; heat-shock proteins; molecular chaperones; non-coding RNA; proteostasis; tRNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.001
  13. Biochemistry. 2024 Jan 24.
    Intrinsically Disordered Regions in the Transcription Factor MYC:MAX Modulate DNA Binding via Intramolecular Interactions.
    Stefan Schütz, Christian Bergsdorf, Sandra Hänni-Holzinger, Andreas Lingel, Martin Renatus, Alvar D Gossert, Wolfgang Jahnke.
      The basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor (TF) MYC is in large part an intrinsically disordered oncoprotein. In complex with its obligate heterodimerization partner MAX, MYC preferentially binds E-Box DNA sequences (CANNTG). At promoters containing these sequence motifs, MYC controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis. A vast network of proteins in turn regulates MYC function via intermolecular interactions. In this work, we establish another layer of MYC regulation by intramolecular interactions. We used nuclear magnetic resonance (NMR) spectroscopy to identify and map multiple binding sites for the C-terminal MYC:MAX DNA-binding domain (DBD) on the intrinsically disordered regions (IDRs) in the MYC N-terminus. We find that these binding events in trans are driven by electrostatic attraction, that they have distinct affinities, and that they are competitive with DNA binding. Thereby, we observe the strongest effects for the N-terminal MYC box 0 (Mb0), a conserved motif involved in MYC transactivation and target gene induction. We prepared recombinant full-length MYC:MAX complex and demonstrate that the interactions identified in this work are also relevant in cis, i.e., as intramolecular interactions. These findings are supported by surface plasmon resonance (SPR) experiments, which revealed that intramolecular IDR:DBD interactions in MYC decelerate the association of MYC:MAX complexes to DNA. Our work offers new insights into how bHLH-LZ TFs are regulated by intramolecular interactions, which open up new possibilities for drug discovery.
    DOI:  https://doi.org/10.1021/acs.biochem.3c00608
  14. Elife. 2024 Jan 23. pii: RP90846. [Epub ahead of print]12
    Cis-regulatory modes of Ultrabithorax inactivation in butterfly forewings.
    Amruta Tendolkar, Anyi Mazo-Vargas, Luca Livraghi, Joseph J Hanly, Kelsey C Van Horne, Lawrence E Gilbert, Arnaud Martin.
      Hox gene clusters encode transcription factors that drive regional specialization during animal development: for example the Hox factor Ubx is expressed in the insect metathoracic (T3) wing appendages and differentiates them from T2 mesothoracic identities. Hox transcriptional regulation requires silencing activities that prevent spurious activation and regulatory crosstalks in the wrong tissues, but this has seldom been studied in insects other than Drosophila, which shows a derived Hox dislocation into two genomic clusters that disjoined Antennapedia (Antp) and Ultrabithorax (Ubx). Here, we investigated how Ubx is restricted to the hindwing in butterflies, amidst a contiguous Hox cluster. By analysing Hi-C and ATAC-seq data in the butterfly Junonia coenia, we show that a Topologically Associated Domain (TAD) maintains a hindwing-enriched profile of chromatin opening around Ubx. This TAD is bordered by a Boundary Element (BE) that separates it from a region of joined wing activity around the Antp locus. CRISPR mutational perturbation of this BE releases ectopic Ubx expression in forewings, inducing homeotic clones with hindwing identities. Further mutational interrogation of two non-coding RNA encoding regions and one putative cis-regulatory module within the Ubx TAD cause rare homeotic transformations in both directions, indicating the presence of both activating and repressing chromatin features. We also describe a series of spontaneous forewing homeotic phenotypes obtained in Heliconius butterflies, and discuss their possible mutational basis. By leveraging the extensive wing specialization found in butterflies, our initial exploration of Ubx regulation demonstrates the existence of silencing and insulating sequences that prevent its spurious expression in forewings.
    Keywords:  Hox; boundary element; butterflies; evo-devo; evolutionary biology; genetics; genomics
    DOI:  https://doi.org/10.7554/eLife.90846
  15. Nat Commun. 2024 Jan 22. 15(1): 667
    The UBP5 histone H2A deubiquitinase counteracts PRCs-mediated repression to regulate Arabidopsis development.
    James Godwin, Mohan Govindasamy, Kiruba Nedounsejian, Eduardo March, Ronan Halton, Clara Bourbousse, Léa Wolff, Antoine Fort, Michal Krzyszton, Jesús López Corrales, Szymon Swiezewski, Fredy Barneche, Daniel Schubert, Sara Farrona.
      Polycomb Repressive Complexes (PRCs) control gene expression through the incorporation of H2Aub and H3K27me3. In recent years, there is increasing evidence of the complexity of PRCs' interaction networks and the interplay of these interactors with PRCs in epigenome reshaping, which is fundamental to understand gene regulatory mechanisms. Here, we identified UBIQUITIN SPECIFIC PROTEASE 5 (UBP5) as a chromatin player able to counteract the deposition of the two PRCs' epigenetic hallmarks in Arabidopsis thaliana. We demonstrated that UBP5 is a plant developmental regulator based on functional analyses of ubp5-CRISPR Cas9 mutant plants. UBP5 promotes H2A monoubiquitination erasure, leading to transcriptional de-repression. Furthermore, preferential association of UBP5 at PRC2 recruiting motifs and local H3K27me3 gaining in ubp5 mutant plants suggest the existence of functional interplays between UBP5 and PRC2 in regulating epigenome dynamics. In summary, acting as an antagonist of the pivotal epigenetic repressive marks H2Aub and H3K27me3, UBP5 provides novel insights to disentangle the complex regulation of PRCs' activities.
    DOI:  https://doi.org/10.1038/s41467-023-44546-8
  16. Nucleic Acids Res. 2024 Jan 23. pii: gkad1232. [Epub ahead of print]
    Reconstructing DNA methylation maps of ancient populations.
    Arielle Barouch, Yoav Mathov, Eran Meshorer, Benjamin Yakir, Liran Carmel.
      Studying premortem DNA methylation from ancient DNA (aDNA) provides a proxy for ancient gene activity patterns, and hence valuable information on evolutionary changes in gene regulation. Due to statistical limitations, current methods to reconstruct aDNA methylation maps are constrained to high-coverage shotgun samples, which comprise a small minority of available ancient samples. Most samples are sequenced using in-situ hybridization capture sequencing which targets a predefined set of genomic positions. Here, we develop methods to reconstruct aDNA methylation maps of samples that were not sequenced using high-coverage shotgun sequencing, by way of pooling together individuals to obtain a DNA methylation map that is characteristic of a population. We show that the resulting DNA methylation maps capture meaningful biological information and allow for the detection of differential methylation across populations. We offer guidelines on how to carry out comparative studies involving ancient populations, and how to control the rate of falsely discovered differentially methylated regions. The ability to reconstruct DNA methylation maps of past populations allows for the development of a whole new frontier in paleoepigenetic research, tracing DNA methylation changes throughout human history, using data from thousands of ancient samples.
    DOI:  https://doi.org/10.1093/nar/gkad1232
  17. PLoS Comput Biol. 2024 Jan 24. 20(1): e1011799
    A genome-wide comprehensive analysis of nucleosome positioning in yeast.
    Leo Zeitler, Kévin André, Adriana Alberti, Cyril Denby Wilkes, Julie Soutourina, Arach Goldar.
      In eukaryotic cells, the one-dimensional DNA molecules need to be tightly packaged into the spatially constraining nucleus. Folding is achieved on its lowest level by wrapping the DNA around nucleosomes. Their arrangement regulates other nuclear processes, such as transcription and DNA repair. Despite strong efforts to study nucleosome positioning using Next Generation Sequencing (NGS) data, the mechanism of their collective arrangement along the gene body remains poorly understood. Here, we classify nucleosome distributions of protein-coding genes in Saccharomyces cerevisiae according to their profile similarity and analyse their differences using functional Principal Component Analysis. By decomposing the NGS signals into their main descriptive functions, we compared wild type and chromatin remodeler-deficient strains, keeping position-specific details preserved whilst considering the nucleosome arrangement as a whole. A correlation analysis with other genomic properties, such as gene size and length of the upstream Nucleosome Depleted Region (NDR), identified key factors that influence the nucleosome distribution. We reveal that the RSC chromatin remodeler-which is responsible for NDR maintenance-is indispensable for decoupling nucleosome arrangement within the gene from positioning outside, which interfere in rsc8-depleted conditions. Moreover, nucleosome profiles in chd1Δ strains displayed a clear correlation with RNA polymerase II presence, whereas wild type cells did not indicate a noticeable interdependence. We propose that RSC is pivotal for global nucleosome organisation, whilst Chd1 plays a key role for maintaining local arrangement.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011799
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