bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022–09–18
sixteen papers selected by
Connor Rogerson, University of Cambridge
  1. Cohesin is required for long-range enhancer action at the Shh locus.
  2. Developmental and housekeeping transcriptional programs in Drosophila require distinct chromatin remodelers.
  3. Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila.
  4. ISSAAC-seq enables sensitive and flexible multimodal profiling of chromatin accessibility and gene expression in single cells.
  5. Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner.
  6. Control of ribosomal RNA synthesis by hematopoietic transcription factors.
  7. Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.
  8. Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia.
  9. Trypanosoma brucei histones are heavily modified with combinatorial post-translational modifications and mark Pol II transcription start regions with hyperacetylated H2A.
  10. PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development.
  11. Global chromatin accessibility profiling analysis reveals a chronic activation state in aged muscle stem cells.
  12. TAMC: A deep-learning approach to predict motif-centric transcriptional factor binding activity based on ATAC-seq profile.
  13. Sociosexual behavior requires both activating and repressive roles of Tfap2e/AP-2ε in vomeronasal sensory neurons.
  14. Nucleosome sliding can influence the spreading of histone modifications.
  15. Double-strand break toxicity is chromatin context independent.
  16. Identification of a transcriptional signature found in multiple models of ASD and related disorders.
  1. Nat Struct Mol Biol. 2022 Sep 12.
    Cohesin is required for long-range enhancer action at the Shh locus.
    Lauren Kane, Iain Williamson, Ilya M Flyamer, Yatendra Kumar, Robert E Hill, Laura A Lettice, Wendy A Bickmore.
      The regulatory landscapes of developmental genes in mammals can be complex, with enhancers spread over many hundreds of kilobases. It has been suggested that three-dimensional genome organization, particularly topologically associating domains formed by cohesin-mediated loop extrusion, is important for enhancers to act over such large genomic distances. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment, here we show that cohesin, but not CTCF, is required for activation of the target gene Shh by distant enhancers in mouse embryonic stem cells. Cohesin is not required for activation directly at the promoter or by an enhancer located closer to the Shh gene. Our findings support the hypothesis that chromatin compaction via cohesin-mediated loop extrusion allows for genes to be activated by enhancers that are located many hundreds of kilobases away in the linear genome and suggests that cohesin is dispensable for enhancers located more proximally.
    DOI:  https://doi.org/10.1038/s41594-022-00821-8
  2. Mol Cell. 2022 Sep 13. pii: S1097-2765(22)00808-5. [Epub ahead of print]
    Developmental and housekeeping transcriptional programs in Drosophila require distinct chromatin remodelers.
    Oliver Hendy, Leonid Serebreni, Katharina Bergauer, Felix Muerdter, Lukas Huber, Filip Nemčko, Alexander Stark.
      Gene transcription is a highly regulated process in all animals. In Drosophila, two major transcriptional programs, housekeeping and developmental, have promoters with distinct regulatory compatibilities and nucleosome organization. However, it remains unclear how the differences in chromatin structure relate to the distinct regulatory properties and which chromatin remodelers are required for these programs. Using rapid degradation of core remodeler subunits in Drosophila melanogaster S2 cells, we demonstrate that developmental gene transcription requires SWI/SNF-type complexes, primarily to maintain distal enhancer accessibility. In contrast, wild-type-level housekeeping gene transcription requires the Iswi and Ino80 remodelers to maintain nucleosome positioning and phasing at promoters. These differential remodeler dependencies relate to different DNA-sequence-intrinsic nucleosome affinities, which favor a default ON state for housekeeping but a default OFF state for developmental gene transcription. Overall, our results demonstrate how different transcription-regulatory strategies are implemented by DNA sequence, chromatin structure, and remodeler activity.
    Keywords:  AID; Ino80; Iswi; STARR-seq; SWI/SNF; auxin-inducible degradation; chromatin remodeling; enhancers; gene regulation; promoters; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.019
  3. Nat Commun. 2022 Sep 14. 13(1): 5375
    Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila.
    Markus Götz, Olivier Messina, Sergio Espinola, Jean-Bernard Fiche, Marcelo Nollmann.
      The spatial organization of chromatin at the scale of topologically associating domains (TADs) and below displays large cell-to-cell variations. Up until now, how this heterogeneity in chromatin conformation is shaped by chromatin condensation, TAD insulation, and transcription has remained mostly elusive. Here, we used Hi-M, a multiplexed DNA-FISH imaging technique providing developmental timing and transcriptional status, to show that the emergence of TADs at the ensemble level partially segregates the conformational space explored by single nuclei during the early development of Drosophila embryos. Surprisingly, a substantial fraction of nuclei display strong insulation even before TADs emerge. Moreover, active transcription within a TAD leads to minor changes to the local inter- and intra-TAD chromatin conformation in single nuclei and only weakly affects insulation to the neighboring TAD. Overall, our results indicate that multiple parameters contribute to shaping the chromatin architecture of single nuclei at the TAD scale.
    DOI:  https://doi.org/10.1038/s41467-022-32973-y
  4. Nat Methods. 2022 Sep 15.
    ISSAAC-seq enables sensitive and flexible multimodal profiling of chromatin accessibility and gene expression in single cells.
    Wei Xu, Weilong Yang, Yunlong Zhang, Yawen Chen, Ni Hong, Qian Zhang, Xuefei Wang, Yukun Hu, Kun Song, Wenfei Jin, Xi Chen.
      Joint profiling of chromatin accessibility and gene expression from the same single cell provides critical information about cell types in a tissue and cell states during a dynamic process. Here, we develop in situ sequencing hetero RNA-DNA-hybrid after assay for transposase-accessible chromatin-sequencing (ISSAAC-seq), a highly sensitive and flexible single-cell multi-omics method to interrogate chromatin accessibility and gene expression from the same single nucleus. We demonstrated that ISSAAC-seq is sensitive and provides high quality data with orders of magnitude more features than existing methods. Using the joint profiles from over 10,000 nuclei from the mouse cerebral cortex, we uncovered major and rare cell types and cell-type specific regulatory elements and identified heterogeneity at the chromatin level within established cell types defined by gene expression. Finally, we revealed distinct dynamics and relationships of gene expression and chromatin accessibility during an oligodendrocyte maturation trajectory.
    DOI:  https://doi.org/10.1038/s41592-022-01601-4
  5. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01157-3. [Epub ahead of print]40(11): 111329
    Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner.
    José Miguel Fernández-Justel, Cristina Santa-María, Sara Martín-Vírgala, Shreya Ramesh, Alberto Ferrera-Lagoa, Mónica Salinas-Pena, Javier Isoler-Alcaraz, Magdalena M Maslon, Albert Jordan, Javier F Cáceres, María Gómez.
      Linker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we identify a function of histone H1 in chromatin structure and transcription using a range of genomic approaches. In the absence of histone H1, there is an increase in the transcription of non-coding RNAs, together with reduced levels of m6A modification leading to their accumulation on chromatin and causing replication-transcription conflicts. This strongly suggests that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism, and DNA replication to maintain genome performance.
    Keywords:  CP: Molecular biology; R-loops; chromatin RNAs; chromatin conformation; histone H1; lncRNAs; m6A; mESCs; replication-transcription conflicts; replicative stress
    DOI:  https://doi.org/10.1016/j.celrep.2022.111329
  6. Mol Cell. 2022 Sep 09. pii: S1097-2765(22)00847-4. [Epub ahead of print]
    Control of ribosomal RNA synthesis by hematopoietic transcription factors.
    Charles Antony, Subin S George, Justin Blum, Patrick Somers, Chelsea L Thorsheim, Dexter J Wu-Corts, Yuxi Ai, Long Gao, Kaosheng Lv, Michel G Tremblay, Tom Moss, Kai Tan, Jeremy E Wilusz, Austen R D Ganley, Maxim Pimkin, Vikram R Paralkar.
      Ribosomal RNAs (rRNAs) are the most abundant cellular RNAs, and their synthesis from rDNA repeats by RNA polymerase I accounts for the bulk of all transcription. Despite substantial variation in rRNA transcription rates across cell types, little is known about cell-type-specific factors that bind rDNA and regulate rRNA transcription to meet tissue-specific needs. Using hematopoiesis as a model system, we mapped about 2,200 ChIP-seq datasets for 250 transcription factors (TFs) and chromatin proteins to human and mouse rDNA and identified robust binding of multiple TF families to canonical TF motifs on rDNA. Using a 47S-FISH-Flow assay developed for nascent rRNA quantification, we demonstrated that targeted degradation of C/EBP alpha (CEBPA), a critical hematopoietic TF with conserved rDNA binding, caused rapid reduction in rRNA transcription due to reduced RNA Pol I occupancy. Our work identifies numerous potential rRNA regulators and provides a template for dissection of TF roles in rRNA transcription.
    Keywords:  CEBPa; FISH; Polr1; RNA Pol I; RNA polymerase I; dTAG; degron; hematopoiesis; rDNA; rRNA; ribosome biogenesis; transcription factor
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.027
  7. Nucleic Acids Res. 2022 Sep 12. pii: gkac735. [Epub ahead of print]
    Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.
    Yuko Hino, Katsuya Nagaoka, Shinya Oki, Kan Etoh, Shinjiro Hino, Mitsuyoshi Nakao.
      Nucleus-mitochondria crosstalk is essential for cellular and organismal homeostasis. Although anterograde (nucleus-to-mitochondria) pathways have been well characterized, retrograde (mitochondria-to-nucleus) pathways remain to be clarified. Here, we found that mitochondrial dysfunction triggered a retrograde signaling via unique transcriptional and chromatin factors in hepatic cells. Our transcriptomic analysis revealed that the loss of mitochondrial transcription factor A led to mitochondrial dysfunction and dramatically induced expression of amphiregulin (AREG) and other secretory protein genes. AREG expression was also induced by various mitochondria stressors and was upregulated in murine liver injury models, suggesting that AREG expression is a hallmark of mitochondrial damage. Using epigenomic and informatic approaches, we identified that mitochondrial dysfunction-responsive enhancers of AREG gene were activated by c-JUN/YAP1/TEAD axis and were repressed by chromatin remodeler BRG1. Furthermore, while mitochondrial dysfunction-activated enhancers were enriched with JUN and TEAD binding motifs, the repressed enhancers possessed the binding motifs for hepatocyte nuclear factor 4α, suggesting that both stress responsible and cell type-specific enhancers were reprogrammed. Our study revealed that c-JUN and YAP1-mediated enhancer activation shapes the mitochondrial stress-responsive phenotype, which may shift from metabolism to stress adaptation including protein secretion under such stressed conditions.
    DOI:  https://doi.org/10.1093/nar/gkac735
  8. Nat Commun. 2022 Sep 14. 13(1): 5401
    Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia.
    Xujie Zhao, Ping Wang, Jonathan D Diedrich, Brandon Smart, Noemi Reyes, Satoshi Yoshimura, Jingliao Zhang, Wentao Yang, Kelly Barnett, Beisi Xu, Zhenhua Li, Xin Huang, Jiyang Yu, Kristine Crews, Allen Eng Juh Yeoh, Marina Konopleva, Chia-Lin Wei, Ching-Hon Pui, Daniel Savic, Jun J Yang.
      FLT3 is an attractive therapeutic target in acute lymphoblastic leukemia (ALL) but the mechanism for its activation in this cancer is incompletely understood. Profiling global gene expression in large ALL cohorts, we identify over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discover an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There is also a global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells. Downregulation of ZNF384 blunts FLT3 activation and decreases ALL cell sensitivity to FLT3 inhibitor gilteritinib in vitro. In patient-derived xenograft models of ZNF384-rearranged ALL, gilteritinib exhibits significant anti-leukemia efficacy as a monotherapy in vivo. Collectively, our results provide insights into FLT3 regulation in ALL and point to potential genomics-guided targeted therapy for this patient population.
    DOI:  https://doi.org/10.1038/s41467-022-33143-w
  9. Nucleic Acids Res. 2022 Sep 12. pii: gkac759. [Epub ahead of print]
    Trypanosoma brucei histones are heavily modified with combinatorial post-translational modifications and mark Pol II transcription start regions with hyperacetylated H2A.
    Johannes P Maree, Andrey Tvardovskiy, Tina Ravnsborg, Ole N Jensen, Gloria Rudenko, Hugh-G Patterton.
      Trypanosomes diverged from the main eukaryotic lineage about 600 million years ago, and display some unusual genomic and epigenetic properties that provide valuable insight into the early processes employed by eukaryotic ancestors to regulate chromatin-mediated functions. We analysed Trypanosoma brucei core histones by high mass accuracy middle-down mass spectrometry to map core histone post-translational modifications (PTMs) and elucidate cis-histone combinatorial PTMs (cPTMs). T. brucei histones are heavily modified and display intricate cPTMs patterns, with numerous hypermodified cPTMs that could contribute to the formation of non-repressive euchromatic states. The Trypanosoma brucei H2A C-terminal tail is hyperacetylated, containing up to five acetylated lysine residues. MNase-ChIP-seq revealed a striking enrichment of hyperacetylated H2A at Pol II transcription start regions, and showed that H2A histones that are hyperacetylated in different combinations localised to different genomic regions, suggesting distinct epigenetic functions. Our genomics and proteomics data provide insight into the complex epigenetic mechanisms used by this parasite to regulate a genome that lacks the transcriptional control mechanisms found in later-branched eukaryotes. The findings further demonstrate the complexity of epigenetic mechanisms that were probably shared with the last eukaryotic common ancestor.
    DOI:  https://doi.org/10.1093/nar/gkac759
  10. Commun Biol. 2022 Sep 14. 5(1): 961
    PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development.
    Xinhui Zhao, Boris Bartholdy, Yukiya Yamamoto, Erica K Evans, Meritxell Alberich-Jordà, Philipp B Staber, Touati Benoukraf, Pu Zhang, Junyan Zhang, Bon Q Trinh, John D Crispino, Trang Hoang, Mahmoud A Bassal, Daniel G Tenen.
      The Ets transcription factor PU.1 is essential for inducing the differentiation of monocytes, macrophages, and B cells in fetal liver and adult bone marrow. PU.1 controls hematopoietic differentiation through physical interactions with other transcription factors, such as C/EBPα and the AP-1 family member c-Jun. We found that PU.1 recruits c-Jun to promoters without the AP-1 binding sites. To address the functional importance of this interaction, we generated PU.1 point mutants that do not bind c-Jun while maintaining normal DNA binding affinity. These mutants lost the ability to transactivate a target reporter that requires a physical PU.1-c-Jun interaction, and did not induce monocyte/macrophage differentiation of PU.1-deficient cells. Knock-in mice carrying these point mutations displayed an almost complete block in hematopoiesis and perinatal lethality. While the PU.1 mutants were expressed in hematopoietic stem and early progenitor cells, myeloid differentiation was severely blocked, leading to an almost complete loss of mature hematopoietic cells. Differentiation into mature macrophages could be restored by expressing PU.1 mutant fused to c-Jun, demonstrating that a physical PU.1-c-Jun interaction is crucial for the transactivation of PU.1 target genes required for myeloid commitment and normal PU.1 function in vivo during macrophage differentiation.
    DOI:  https://doi.org/10.1038/s42003-022-03888-7
  11. iScience. 2022 Sep 16. 25(9): 104954
    Global chromatin accessibility profiling analysis reveals a chronic activation state in aged muscle stem cells.
    Anqi Dong, Jing Liu, Kangning Lin, Wenshu Zeng, Wai-Kin So, Shenyuan Hu, Tom H Cheung.
      Regulation of chromatin accessibility is critical for cell fate decisions. Chromatin structure responds to extrinsic environments rapidly. The traditional adult stem cell isolation approach requires tissue dissociation, which triggers stem cell activation and leads to alterations in chromatin structure. To preserve the in vivo chromatin states, we utilized the PFA-perfusion-based isolation approach and characterized the DNA regulatory landscapes during muscle stem cell quiescence exit and aging. We showed that aged SCs display a chronically activated chromatin signature. Detailed analysis of the chromatin accessibility profiles identified key enhancer elements for SC quiescence. Constant activation of the enhancer elements promotes stemness and prevents SCs from differentiation, whereas genetic deletion causes cell-cycle arrest and leads to defects in activation. Our comprehensive characterization of the chromatin accessibility and transcriptomic landscapes in SC quiescence and aging broadens our understanding of these processes and identifies key distal regulatory elements for SC function.
    Keywords:  Cell biology; Omics; Stem cells research; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104954
  12. PLoS Comput Biol. 2022 Sep 12. 18(9): e1009921
    TAMC: A deep-learning approach to predict motif-centric transcriptional factor binding activity based on ATAC-seq profile.
    Tianqi Yang, Ricardo Henao.
      Determining transcriptional factor binding sites (TFBSs) is critical for understanding the molecular mechanisms regulating gene expression in different biological conditions. Biological assays designed to directly mapping TFBSs require large sample size and intensive resources. As an alternative, ATAC-seq assay is simple to conduct and provides genomic cleavage profiles that contain rich information for imputing TFBSs indirectly. Previous footprint-based tools are inheritably limited by the accuracy of their bias correction algorithms and the efficiency of their feature extraction models. Here we introduce TAMC (Transcriptional factor binding prediction from ATAC-seq profile at Motif-predicted binding sites using Convolutional neural networks), a deep-learning approach for predicting motif-centric TF binding activity from paired-end ATAC-seq data. TAMC does not require bias correction during signal processing. By leveraging a one-dimensional convolutional neural network (1D-CNN) model, TAMC make predictions based on both footprint and non-footprint features at binding sites for each TF and outperforms existing footprinting tools in TFBS prediction particularly for ATAC-seq data with limited sequencing depth.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009921
  13. Elife. 2022 Sep 16. pii: e77259. [Epub ahead of print]11
    Sociosexual behavior requires both activating and repressive roles of Tfap2e/AP-2ε in vomeronasal sensory neurons.
    Jennifer M Lin, Tyler A Mitchell, Megan Rothstein, Alison Pehl, Ed Zandro M Taroc, Raghu R Katreddi, Katherine E Parra, Damian G Zuloaga, Marcos Simoes-Costa, Paolo Emanuele Forni.
      Neuronal identity dictates the position in an epithelium, and the ability to detect, process, and transmit specific signals to specified targets. Transcription factors (TFs) determine cellular identity via direct modulation of genetic transcription and recruiting chromatin modifiers. However, our understanding of the mechanisms that define neuronal identity and their magnitude remain a critical barrier to elucidate the etiology of congenital and neurodegenerative disorders. The rodent vomeronasal organ provides a unique system to examine in detail the molecular mechanisms underlying the differentiation and maturation of chemosensory neurons. Here we demonstrated that the identity of postmitotic/maturing vomeronasal sensory neurons (VSNs), and vomeronasal dependent behaviors can be reprogrammed through the rescue of Tfap2e/AP-2e expression in the Tfap2eNull mice, and partially reprogrammed by inducing ectopic Tfap2e expression in mature apical VSNs. We suggest that the transcription factor Tfap2e can reprogram VSNs bypassing cellular plasticity restrictions, and that it directly controls the expression of batteries of vomeronasal genes.
    Keywords:  developmental biology; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.77259
  14. Phys Rev E. 2022 Aug;106(2-1): 024408
    Nucleosome sliding can influence the spreading of histone modifications.
    Shantanu Kadam, Tripti Bameta, Ranjith Padinhateeri.
      Nucleosomes are the fundamental building blocks of chromatin that not only help in the folding of chromatin, but also in carrying epigenetic information. It is known that nucleosome sliding is responsible for dynamically organizing chromatin structure and the resulting gene regulation. Since sliding can move two neighboring nucleosomes physically close or away, can it play a role in the spreading of histone modifications? We investigate this by simulating a stochastic model that couples nucleosome dynamics with the kinetics of histone modifications. We show that the sliding of nucleosomes can affect the modification pattern as well as the time it takes to modify a given region of chromatin. Exploring different nucleosome densities and modification kinetic parameters, we show that nucleosome sliding can be important for creating histone modification domains. Our model predicts that nucleosome density coupled with sliding dynamics can create an asymmetric histone modification profile around regulatory regions. We also compute the probability distribution of modified nucleosomes and relaxation kinetics of modifications. Our predictions are comparable with known experimental results.
    DOI:  https://doi.org/10.1103/PhysRevE.106.024408
  15. Nucleic Acids Res. 2022 Sep 15. pii: gkac758. [Epub ahead of print]
    Double-strand break toxicity is chromatin context independent.
    Anoek Friskes, Lisa Koob, Lenno Krenning, Tesa M Severson, Emma S Koeleman, Xabier Vergara, Michael Schubert, Jeroen van den Berg, Bastiaan Evers, Anna G Manjón, Stacey Joosten, Yongsoo Kim, Wilbert Zwart, René H Medema.
      Cells respond to double-strand breaks (DSBs) by activating DNA damage response pathways, including cell cycle arrest. We have previously shown that a single double-strand break generated via CRISPR/Cas9 is sufficient to delay cell cycle progression and compromise cell viability. However, we also found that the cellular response to DSBs can vary, independent of the number of lesions. This implies that not all DSBs are equally toxic, and raises the question if the location of a single double-strand break could influence its toxicity. To systematically investigate if DSB-location is a determinant of toxicity we performed a CRISPR/Cas9 screen targeting 6237 single sites in the human genome. Next, we developed a data-driven framework to design CRISPR/Cas9 sgRNA (crRNA) pools targeting specific chromatin features. The chromatin context was defined using ChromHMM states, Lamin-B1 DAM-iD, DNAseI hypersensitivity, and RNA-sequencing data. We computationally designed 6 distinct crRNA pools, each containing 10 crRNAs targeting the same chromatin state. We show that the toxicity of a DSB is highly similar across the different ChromHMM states. Rather, we find that the major determinants of toxicity of a sgRNA are cutting efficiency and off-target effects. Thus, chromatin features have little to no effect on the toxicity of a single CRISPR/Cas9-induced DSB.
    DOI:  https://doi.org/10.1093/nar/gkac758
  16. Genome Res. 2022 Sep 14.
    Identification of a transcriptional signature found in multiple models of ASD and related disorders.
    Samuel Thudium, Katherine Palozola, Éloïse L'Her, Erica Korb.
      Epigenetic regulation plays a critical role in many neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). In particular, many such disorders are the result of mutations in genes that encode chromatin-modifying proteins. However, although these disorders share many features, it is unclear whether they also share gene expression disruptions resulting from the aberrant regulation of chromatin. We examined five chromatin modifiers that are all linked to ASD despite their different roles in regulating chromatin. Specifically, we depleted ASH1L, CHD8, CREBBP, EHMT1, and NSD1 in parallel in a highly controlled neuronal culture system. We then identified sets of shared genes, or transcriptional signatures, that are differentially expressed following loss of multiple ASD-linked chromatin modifiers. We examined the functions of genes within the transcriptional signatures and found an enrichment in many neurotransmitter transport genes and activity-dependent genes. In addition, these genes are enriched for specific chromatin features such as bivalent domains that allow for highly dynamic regulation of gene expression. The down-regulated transcriptional signature is also observed within multiple mouse models of NDDs that result in ASD, but not those only associated with intellectual disability. Finally, the down-regulated transcriptional signature can distinguish between control and idiopathic ASD patient iPSC-derived neurons as well as postmortem tissue, demonstrating that this gene set is relevant to the human disorder. This work identifies a transcriptional signature that is found within many neurodevelopmental syndromes, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in ASD.
    DOI:  https://doi.org/10.1101/gr.276591.122
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