bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2022–04–17
twenty-two papers selected by
Connor Rogerson, University of Cambridge, MRC Cancer Unit
  1. Nonlinear control of transcription through enhancer-promoter interactions.
  2. RBBP4 dysfunction reshapes the genomic landscape of H3K27 methylation and acetylation and disrupts gene expression.
  3. BRD2 compartmentalizes the accessible genome.
  4. Sequential enhancer state remodelling defines human germline competence and specification.
  5. YY1 safeguard multidimensional epigenetic landscape associated with extended pluripotency.
  6. ProbC: joint modeling of epigenome and transcriptome effects in 3D genome.
  7. H3K27me3 conditions chemotolerance in triple-negative breast cancer.
  8. Inferring mammalian tissue-specific regulatory conservation by predicting tissue-specific differences in open chromatin.
  9. Evolution of binding preferences among whole-genome duplicated transcription factors.
  10. nMOWChIP-seq: low-input genome-wide mapping of non-histone targets.
  11. Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging.
  12. Loss of PBRM1 alters promoter histone modifications and activates ALDH1A1 to drive renal cell carcinoma.
  13. SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.
  14. Single nucleus multi-omics identifies human cortical cell regulatory genome diversity.
  15. DUX4 is a multifunctional factor priming human embryonic genome activation.
  16. Transcription factors KLF15 and PPARδ cooperatively orchestrate genome-wide regulation of lipid metabolism in skeletal muscle.
  17. DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis.
  18. GenomicDistributions: fast analysis of genomic intervals with Bioconductor.
  19. Inducible and reversible RNA N6-methyladenosine editing.
  20. Non-coding RNA LEVER sequestration of PRC2 can mediate long range gene regulation.
  21. Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers.
  22. WashU Epigenome Browser update 2022.
  1. Nature. 2022 Apr 13.
    Nonlinear control of transcription through enhancer-promoter interactions.
    Jessica Zuin, Gregory Roth, Yinxiu Zhan, Julie Cramard, Josef Redolfi, Ewa Piskadlo, Pia Mach, Mariya Kryzhanovska, Gergely Tihanyi, Hubertus Kohler, Mathias Eder, Christ Leemans, Bas van Steensel, Peter Meister, Sebastien Smallwood, Luca Giorgetti.
      Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs)1-4. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Mathematical modelling suggests that nonlinearity might arise from transient enhancer-promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation.
    DOI:  https://doi.org/10.1038/s41586-022-04570-y
  2. G3 (Bethesda). 2022 Apr 13. pii: jkac082. [Epub ahead of print]
    RBBP4 dysfunction reshapes the genomic landscape of H3K27 methylation and acetylation and disrupts gene expression.
    Weipeng Mu, Noel S Murcia, Keriayn N Smith, Debashish U Menon, Della Yee, Terry Magnuson.
      RBBP4 is a subunit of the chromatin remodeling complexes known as Polycomb repressive complex 2 (PRC2) and HDAC1/2-containing complexes. These complexes are responsible for histone H3 lysine 27 (H3K27) methylation and deacetylation, respectively. How RBBP4 modulates the functions of these complexes remains largely unknown. We generated viable Rbbp4 mutant alleles in mouse embryonic stem cell lines by CRISPR-Cas9. The mutations disrupted PRC2 assembly and H3K27me3 establishment on target chromatin and altered H3K27 acetylation genome wide. Moreover, Rbbp4 mutant cells underwent dramatic changes in transcriptional profiles closely tied to the deregulation of H3K27ac. The alteration of H3K27ac due to RBBP4 dysfunction occurred on numerous cis-regulatory elements, especially putative enhancers. These data suggest that RBBP4 plays a central role in regulating H3K27 methylation and acetylation to modulate gene expression.
    Keywords:  Polycomb-Group proteins; enhancer; histone acetylation; histone methylation; super-enhancer; transcriptional regulation
    DOI:  https://doi.org/10.1093/g3journal/jkac082
  3. Nat Genet. 2022 Apr;54(4): 481-491
    BRD2 compartmentalizes the accessible genome.
    Liangqi Xie, Peng Dong, Yifeng Qi, Tsung-Han S Hsieh, Brian P English, SeolKyoung Jung, Xingqi Chen, Margherita De Marzio, Rafael Casellas, Howard Y Chang, Bin Zhang, Robert Tjian, Zhe Liu.
      Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active chromatin after cohesin loss. This activity is independent of transcription but requires BRD2 to recognize acetylated targets through its double bromodomain and interact with binding partners with its low-complexity domain. Notably, genome compartmentalization mediated by BRD2 is antagonized on the one hand by cohesin and on the other hand by the BET homolog protein BRD4, both of which inhibit BRD2 binding to chromatin. Polymer simulation of our data supports a BRD2-cohesin interplay model of nuclear topology, in which genome compartmentalization results from a competition between loop extrusion and chromatin-state-specific affinity interactions.
    DOI:  https://doi.org/10.1038/s41588-022-01044-9
  4. Nat Cell Biol. 2022 Apr 11.
    Sequential enhancer state remodelling defines human germline competence and specification.
    Walfred W C Tang, Aracely Castillo-Venzor, Wolfram H Gruhn, Toshihiro Kobayashi, Christopher A Penfold, Michael D Morgan, Dawei Sun, Naoko Irie, M Azim Surani.
      Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation. We show that morphogen-induced remodelling of mesendoderm enhancers transiently confers the competence for hPGC fate, but further activation favours mesoderm and endoderm fates. Consistently, reducing the expression of the mesendodermal transcription factor OTX2 promotes the PGC fate. In hPGCs, SOX17 and TFAP2C initiate activation of enhancers to establish a core germline programme, including the transcriptional repressor PRDM1 and pluripotency factors POU5F1 and NANOG. We demonstrate that SOX17 enhancers are the critical components in the regulatory circuitry of germline competence. Furthermore, activation of upstream cis-regulatory elements by an optimized CRISPR activation system is sufficient for hPGC specification. We reveal an enhancer-linked germline transcription factor network that provides the basis for the evolutionary divergence of mammalian germlines.
    DOI:  https://doi.org/10.1038/s41556-022-00878-z
  5. Nucleic Acids Res. 2022 Apr 15. pii: gkac230. [Epub ahead of print]
    YY1 safeguard multidimensional epigenetic landscape associated with extended pluripotency.
    Xiaotao Dong, Rong Guo, Tianrong Ji, Jie Zhang, Jun Xu, Yaoyi Li, Yingliang Sheng, Yuxiang Wang, Ke Fang, Yulin Wen, Bei Liu, Gongcheng Hu, Hongkui Deng, Hongjie Yao.
      Although extended pluripotent stem cells (EPSCs) have the potential to form both embryonic and extraembryonic lineages, how their transcriptional regulatory mechanism differs from that of embryonic stem cells (ESCs) remains unclear. Here, we discovered that YY1 binds to specific open chromatin regions in EPSCs. Yy1 depletion in EPSCs leads to a gene expression pattern more similar to that of ESCs than control EPSCs. Moreover, Yy1 depletion triggers a series of epigenetic crosstalk activities, including changes in DNA methylation, histone modifications and high-order chromatin structures. Yy1 depletion in EPSCs disrupts the enhancer-promoter (EP) interactions of EPSC-specific genes, including Dnmt3l. Yy1 loss results in DNA hypomethylation and dramatically reduces the enrichment of H3K4me3 and H3K27ac on the promoters of EPSC-specific genes by upregulating the expression of Kdm5c and Hdac6 through facilitating the formation of CCCTC-binding factor (CTCF)-mediated EP interactions surrounding their loci. Furthermore, single-cell RNA sequencing (scRNA-seq) experiments revealed that YY1 is required for the derivation of extraembryonic endoderm (XEN)-like cells from EPSCs in vitro. Together, this study reveals that YY1 functions as a key regulator of multidimensional epigenetic crosstalk associated with extended pluripotency.
    DOI:  https://doi.org/10.1093/nar/gkac230
  6. BMC Genomics. 2022 Apr 09. 23(1): 287
    ProbC: joint modeling of epigenome and transcriptome effects in 3D genome.
    Emre Sefer.
       BACKGROUND: Hi-C and its high nucleosome resolution variant Micro-C provide a window into the spatial packing of a genome in 3D within the cell. Even though both techniques do not directly depend on the binding of specific antibodies, previous work has revealed enriched interactions and domain structures around multiple chromatin marks; epigenetic modifications and transcription factor binding sites. However, the joint impact of chromatin marks in Hi-C and Micro-C interactions have not been globally characterized, which limits our understanding of 3D genome characteristics. An emerging question is whether it is possible to deduce 3D genome characteristics and interactions by integrative analysis of multiple chromatin marks and associate interactions to functionality of the interacting loci.
    RESULT: We come up with a probabilistic method PROBC to decompose Hi-C and Micro-C interactions by known chromatin marks. PROBC is based on convex likelihood optimization, which can directly take into account both interaction existence and nonexistence. Through PROBC, we discover histone modifications (H3K27ac, H3K9me3, H3K4me3, H3K4me1) and CTCF as particularly predictive of Hi-C and Micro-C contacts across cell types and species. Moreover, histone modifications are more effective than transcription factor binding sites in explaining the genome's 3D shape through these interactions. PROBC can successfully predict Hi-C and Micro-C interactions in given species, while it is trained on different cell types or species. For instance, it can predict missing nucleosome resolution Micro-C interactions in human ES cells trained on mouse ES cells only from these 5 chromatin marks with above 0.75 AUC. Additionally, PROBC outperforms the existing methods in predicting interactions across almost all chromosomes.
    CONCLUSION: Via our proposed method, we optimally decompose Hi-C interactions in terms of these chromatin marks at genome and chromosome levels. We find a subset of histone modifications and transcription factor binding sites to be predictive of both Hi-C and Micro-C interactions and TADs across human, mouse, and different cell types. Through learned models, we can predict interactions on species just from chromatin marks for which Hi-C data may be limited.
    Keywords:  Chromatin organization; Epigenetics; Hi-C; Machine learning; Micro-C
    DOI:  https://doi.org/10.1186/s12864-022-08498-5
  7. Nat Genet. 2022 Apr;54(4): 459-468
    H3K27me3 conditions chemotolerance in triple-negative breast cancer.
    Justine Marsolier, Pacôme Prompsy, Adeline Durand, Anne-Marie Lyne, Camille Landragin, Amandine Trouchet, Sabrina Tenreira Bento, Almut Eisele, Sophie Foulon, Léa Baudre, Kevin Grosselin, Mylène Bohec, Sylvain Baulande, Ahmed Dahmani, Laura Sourd, Eric Letouzé, Anne-Vincent Salomon, Elisabetta Marangoni, Leïla Perié, Céline Vallot.
      The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.
    DOI:  https://doi.org/10.1038/s41588-022-01047-6
  8. BMC Genomics. 2022 Apr 11. 23(1): 291
    Inferring mammalian tissue-specific regulatory conservation by predicting tissue-specific differences in open chromatin.
    Irene M Kaplow, Daniel E Schäffer, Morgan E Wirthlin, Alyssa J Lawler, Ashley R Brown, Michael Kleyman, Andreas R Pfenning.
       BACKGROUND: Evolutionary conservation is an invaluable tool for inferring functional significance in the genome, including regions that are crucial across many species and those that have undergone convergent evolution. Computational methods to test for sequence conservation are dominated by algorithms that examine the ability of one or more nucleotides to align across large evolutionary distances. While these nucleotide alignment-based approaches have proven powerful for protein-coding genes and some non-coding elements, they fail to capture conservation of many enhancers, distal regulatory elements that control spatial and temporal patterns of gene expression. The function of enhancers is governed by a complex, often tissue- and cell type-specific code that links combinations of transcription factor binding sites and other regulation-related sequence patterns to regulatory activity. Thus, function of orthologous enhancer regions can be conserved across large evolutionary distances, even when nucleotide turnover is high.
    RESULTS: We present a new machine learning-based approach for evaluating enhancer conservation that leverages the combinatorial sequence code of enhancer activity rather than relying on the alignment of individual nucleotides. We first train a convolutional neural network model that can predict tissue-specific open chromatin, a proxy for enhancer activity, across mammals. Next, we apply that model to distinguish instances where the genome sequence would predict conserved function versus a loss of regulatory activity in that tissue. We present criteria for systematically evaluating model performance for this task and use them to demonstrate that our models accurately predict tissue-specific conservation and divergence in open chromatin between primate and rodent species, vastly out-performing leading nucleotide alignment-based approaches. We then apply our models to predict open chromatin at orthologs of brain and liver open chromatin regions across hundreds of mammals and find that brain enhancers associated with neuron activity have a stronger tendency than the general population to have predicted lineage-specific open chromatin.
    CONCLUSION: The framework presented here provides a mechanism to annotate tissue-specific regulatory function across hundreds of genomes and to study enhancer evolution using predicted regulatory differences rather than nucleotide-level conservation measurements.
    Keywords:  Enhancers; Gene expression evolution; Machine learning; Open chromatin prediction
    DOI:  https://doi.org/10.1186/s12864-022-08450-7
  9. Elife. 2022 Apr 11. pii: e73225. [Epub ahead of print]11
    Evolution of binding preferences among whole-genome duplicated transcription factors.
    Tamar Gera, Felix Jonas, Roye More, Naama Barkai.
      Throughout evolution, new transcription factors (TFs) emerge by gene duplication, promoting growth and rewiring of transcriptional networks. How TF duplicates diverge was studied in a few cases only. To provide a genome-scale view, we considered the set of budding yeast TFs classified as whole-genome duplication (WGD)-retained paralogs (~35% of all specific TFs). Using high-resolution profiling, we find that ~60% of paralogs evolved differential binding preferences. We show that this divergence results primarily from variations outside the DNA-binding domains (DBDs), while DBD preferences remain largely conserved. Analysis of non-WGD orthologs revealed uneven splitting of ancestral preferences between duplicates, and the preferential acquiring of new targets by the least conserved paralog (biased neo/sub-functionalization). Interactions between paralogs were rare, and, when present, occurred through weak competition for DNA-binding or dependency between dimer-forming paralogs. We discuss the implications of our findings for the evolutionary design of transcriptional networks.
    Keywords:  DNA binding; S. cerevisiae; evolutionary biology; functional divergence; gene regulation; genetics; genomics; paralogs; transcription factors; whole genome duplication
    DOI:  https://doi.org/10.7554/eLife.73225
  10. NAR Genom Bioinform. 2022 Jun;4(2): lqac030
    nMOWChIP-seq: low-input genome-wide mapping of non-histone targets.
    Zhengzhi Liu, Lynette B Naler, Yan Zhu, Chengyu Deng, Qiang Zhang, Bohan Zhu, Zirui Zhou, Mimosa Sarma, Alexander Murray, Hehuang Xie, Chang Lu.
      Genome-wide profiling of interactions between genome and various functional proteins is critical for understanding regulatory processes involved in development and diseases. Conventional assays require a large number of cells and high-quality data on tissue samples are scarce. Here we optimized a low-input chromatin immunoprecipitation followed by sequencing (ChIP-seq) technology for profiling RNA polymerase II (Pol II), transcription factor (TF), and enzyme binding at the genome scale. The new approach produces high-quality binding profiles using 1,000-50,000 cells. We used the approach to examine the binding of Pol II and two TFs (EGR1 and MEF2C) in cerebellum and prefrontal cortex of mouse brain and found that their binding profiles are highly reflective of the functional differences between the two brain regions. Our analysis reveals the potential for linking genome-wide TF or Pol II profiles with neuroanatomical origins of brain cells.
    DOI:  https://doi.org/10.1093/nargab/lqac030
  11. Science. 2022 Apr 14. eabn6583
    Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging.
    Michele Gabriele, Hugo B Brandão, Simon Grosse-Holz, Asmita Jha, Gina M Dailey, Claudia Cattoglio, Tsung-Han S Hsieh, Leonid Mirny, Christoph Zechner, Anders S Hansen.
      Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and loop extruding cohesins, but the live dynamics of loop formation and stability remain unknown. Here, we directly visualize chromatin looping at the Fbn2 TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantify looping dynamics by Bayesian inference. Unexpectedly, the Fbn2 loop is both rare and dynamic, with a looped fraction of ~3-6.5% and a median loop lifetime of ~10-30 min. Our results establish that the Fbn2 TAD is highly dynamic, where ~92% of the time cohesin-extruded loops exist within the TAD without bridging both CTCF boundaries. This suggests that single CTCF boundaries rather than the fully CTCF-CTCF looped state may be the primary regulators of functional interactions.
    DOI:  https://doi.org/10.1126/science.abn6583
  12. Mol Cancer Res. 2022 Apr 12. pii: molcanres.1039.2021. [Epub ahead of print]
    Loss of PBRM1 alters promoter histone modifications and activates ALDH1A1 to drive renal cell carcinoma.
    David A Schoenfeld, Royce Zhou, Sakellarios Zairis, William Su, Nicole Steinbach, Deepti Mathur, Ankita Bansal, Alexis L Zachem, Bertilia Tavarez, Dan Hasson, Emily Bernstein, Raul Rabadan, Ramon Parsons.
      Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the tumor suppressor protein PBRM1 (BAF180), as well as ARID2 (BAF200), that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, histone modification ChIP-seq, and ATAC-seq data to show that loss of PBRM1 results in de novo gains in H3K4me3 peaks throughout the epigenome including activation of a retinoic acid biosynthesis and signaling gene signature. We show that one such target gene, ALDH1A1, which regulates a key step in retinoic acid biosynthesis, is consistently upregulated with PBRM1 loss in ccRCC cell lines and primary tumors, as well as non-malignant cells. We further find that ALDH1A1 increases the tumorigenic potential of ccRCC cells. Using biochemical methods, we show that ARID2 remains bound to other PBAF subunits after loss of PBRM1 and is essential for increased ALDH1A1 after loss of PBRM1, whereas other core SWI/SNF components are dispensable, including the ATPase subunit BRG1. In total, this study uses global epigenomic approaches to uncover novel mechanisms of PBRM1 tumor suppression in ccRCC. Implications: This study implicates the SWI/SNF subunit and tumor suppressor PBRM1 in the regulation of promoter histone modifications and retinoic acid biosynthesis and signaling pathways in ccRCC and functionally validates one such target gene, the aldehyde dehydrogenase ALDH1A1.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-1039
  13. Nat Commun. 2022 Apr 12. 13(1): 1968
    SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.
    Vladislav N Nikolov, Dhara Malavia, Takashi Kubota.
      The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.
    DOI:  https://doi.org/10.1038/s41467-022-29591-z
  14. Cell Genom. 2022 Mar 09. pii: 100106. [Epub ahead of print]2(3):
    Single nucleus multi-omics identifies human cortical cell regulatory genome diversity.
    Chongyuan Luo, Hanqing Liu, Fangming Xie, Ethan J Armand, Kimberly Siletti, Trygve E Bakken, Rongxin Fang, Wayne I Doyle, Tim Stuart, Rebecca D Hodge, Lijuan Hu, Bang-An Wang, Zhuzhu Zhang, Sebastian Preissl, Dong-Sung Lee, Jingtian Zhou, Sheng-Yong Niu, Rosa Castanon, Anna Bartlett, Angeline Rivkin, Xinxin Wang, Jacinta Lucero, Joseph R Nery, David A Davis, Deborah C Mash, Rahul Satija, Jesse R Dixon, Sten Linnarsson, Ed Lein, M Margarita Behrens, Bing Ren, Eran A Mukamel, Joseph R Ecker.
      Single-cell technologies measure unique cellular signatures but are typically limited to a single modality. Computational approaches allow the fusion of diverse single-cell data types, but their efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of single cells, we devised single-nucleus methylcytosine, chromatin accessibility, and transcriptome sequencing (snmCAT-seq) and applied it to postmortem human frontal cortex tissue. We developed a cross-validation approach using multi-modal information to validate fine-grained cell types and assessed the effectiveness of computational data fusion methods. Correlation analysis in individual cells revealed distinct relations between methylation and gene expression. Our integrative approach enabled joint analyses of the methylome, transcriptome, chromatin accessibility, and conformation for 63 human cortical cell types. We reconstructed regulatory lineages for cortical cell populations and found specific enrichment of genetic risk for neuropsychiatric traits, enabling the prediction of cell types that are associated with diseases.
    DOI:  https://doi.org/10.1016/j.xgen.2022.100107
  15. iScience. 2022 Apr 15. 25(4): 104137
    DUX4 is a multifunctional factor priming human embryonic genome activation.
    Sanna Vuoristo, Shruti Bhagat, Christel Hydén-Granskog, Masahito Yoshihara, Lisa Gawriyski, Eeva-Mari Jouhilahti, Vipin Ranga, Mahlet Tamirat, Mikko Huhtala, Ida Kirjanov, Sonja Nykänen, Kaarel Krjutškov, Anastassius Damdimopoulos, Jere Weltner, Kosuke Hashimoto, Gaëlle Recher, Sini Ezer, Priit Paluoja, Pauliina Paloviita, Yujiro Takegami, Ai Kanemaru, Karolina Lundin, Tomi T Airenne, Timo Otonkoski, Juha S Tapanainen, Hideya Kawaji, Yasuhiro Murakawa, Thomas R Bürglin, Markku Varjosalo, Mark S Johnson, Timo Tuuri, Shintaro Katayama, Juha Kere.
      Double homeobox 4 (DUX4) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1. We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome.
    Keywords:  biology of human development; developmental biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104137
  16. J Biol Chem. 2022 Apr 09. pii: S0021-9258(22)00366-0. [Epub ahead of print] 101926
    Transcription factors KLF15 and PPARδ cooperatively orchestrate genome-wide regulation of lipid metabolism in skeletal muscle.
    Liyan Fan, David R Sweet, Erica K Fan, Domenick A Prosdocimo, Annmarie Madera, Zhen Jiang, Roshan Padmanabhan, Saptarsi M Haldar, Vinesh Vinayachandran, Mukesh K Jain.
      Skeletal muscle dynamically regulates systemic nutrient homeostasis through transcriptional adaptations to physiological cues. In response to changes in the metabolic environment (e.g., alterations in circulating glucose or lipid levels), networks of transcription factors and co-regulators are recruited to specific genomic loci to fine-tune homeostatic gene regulation. Elucidating these mechanisms is of particular interest as these gene regulatory pathways can serve as potential targets to treat metabolic disease. The zinc-finger transcription factor Krüppel-like factor 15 (KLF15) is a critical regulator of metabolic homeostasis, however its genome-wide distribution in skeletal muscle has not been previously identified. Here, we characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We also identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ co-localize genome-wide, physically interact, and are dependent on one another to exert their transcriptional effects on target genes. These findings reveal that skeletal muscle KLF15 plays a critical role in metabolic adaptation through its direct actions on target genes and interactions with other nodal transcription factors such as PPARδ.
    Keywords:  Kruppel-like factor (KLF); energy metabolism; metabolism; nuclear receptors; peroxisome proliferator-activated receptors; skeletal muscle; transcription; transcription factors
    DOI:  https://doi.org/10.1016/j.jbc.2022.101926
  17. Nat Genet. 2022 Apr;54(4): 469-480
    DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis.
    Mathilde Dura, Aurélie Teissandier, Mélanie Armand, Joan Barau, Clémentine Lapoujade, Pierre Fouchet, Lorraine Bonneville, Mathieu Schulz, Michael Weber, Laura G Baudrin, Sonia Lameiras, Deborah Bourc'his.
      DNA methylation plays a critical role in spermatogenesis, as evidenced by the male sterility of DNA methyltransferase (DNMT) mutant mice. Here, we report a division of labor in the establishment of the methylation landscape of male germ cells and its functions in spermatogenesis. Although DNMT3C is essential for preventing retrotransposons from interfering with meiosis, DNMT3A broadly methylates the genome (with the exception of DNMT3C-dependent retrotransposons) and controls spermatogonial stem cell (SSC) plasticity. By reconstructing developmental trajectories through single-cell RNA sequencing and profiling chromatin states, we found that Dnmt3A mutant SSCs can only self-renew and no longer differentiate in association with spurious enhancer activation that enforces an irreversible stem cell gene program. Our findings therefore highlight a key function of DNA methylation in male fertility: the epigenetic programming of SSC commitment to differentiation and lifelong spermatogenesis supply.
    DOI:  https://doi.org/10.1038/s41588-022-01040-z
  18. BMC Genomics. 2022 Apr 12. 23(1): 299
    GenomicDistributions: fast analysis of genomic intervals with Bioconductor.
    Kristyna Kupkova, Jose Verdezoto Mosquera, Jason P Smith, Michał Stolarczyk, Tessa L Danehy, John T Lawson, Bingjie Xue, John T Stubbs, Nathan LeRoy, Nathan C Sheffield.
       BACKGROUND: Epigenome analysis relies on defined sets of genomic regions output by widely used assays such as ChIP-seq and ATAC-seq. Statistical analysis and visualization of genomic region sets is essential to answer biological questions in gene regulation. As the epigenomics community continues generating data, there will be an increasing need for software tools that can efficiently deal with more abundant and larger genomic region sets. Here, we introduce GenomicDistributions, an R package for fast and easy summarization and visualization of genomic region data.
    RESULTS: GenomicDistributions offers a broad selection of functions to calculate properties of genomic region sets, such as feature distances, genomic partition overlaps, and more. GenomicDistributions functions are meticulously optimized for best-in-class speed and generally outperform comparable functions in existing R packages. GenomicDistributions also offers plotting functions that produce editable ggplot objects. All GenomicDistributions functions follow a uniform naming scheme and can handle either single or multiple region set inputs.
    CONCLUSIONS: GenomicDistributions offers a fast and scalable tool for exploratory genomic region set analysis and visualization. GenomicDistributions excels in user-friendliness, flexibility of outputs, breadth of functions, and computational performance. GenomicDistributions is available from Bioconductor ( https://bioconductor.org/packages/release/bioc/html/GenomicDistributions.html ).
    Keywords:  Bioconductor; Data visualization; Genomic regions; R package; Region set summary
    DOI:  https://doi.org/10.1186/s12864-022-08467-y
  19. Nat Commun. 2022 Apr 12. 13(1): 1958
    Inducible and reversible RNA N6-methyladenosine editing.
    Huaxia Shi, Ying Xu, Na Tian, Ming Yang, Fu-Sen Liang.
      RNA modifications, including N6-methyladenosine (m6A), have been reported to regulate fundamental RNA processes and properties, and directly linked to various human diseases. Methods enabling temporal and transcript/locus-specific editing of specific RNA modifications are essential, but still limited, to dissect the dynamic and context-dependent functions of these epigenetic modifications. Here, we develop a chemically inducible and reversible RNA m6A modification editing platform integrating chemically induced proximity (CIP) and CRISPR methods. We show that m6A editing can be temporally controlled at specific sites of individual RNA transcripts by the addition or removal of the CIP inducer, abscisic acid (ABA), in the system. By incorporating a photo-caged ABA, a light-controlled version of m6A editing platform can be developed. We expect that this platform and strategy can be generally applied to edit other RNA modifications in addition to m6A.
    DOI:  https://doi.org/10.1038/s41467-022-29665-y
  20. Commun Biol. 2022 Apr 11. 5(1): 343
    Non-coding RNA LEVER sequestration of PRC2 can mediate long range gene regulation.
    Wei Wen Teo, Xinang Cao, Chan-Shuo Wu, Hong Kee Tan, Qiling Zhou, Chong Gao, Kim Vanuytsel, Sara S Kumar, George J Murphy, Henry Yang, Li Chai, Daniel G Tenen.
      Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator required for gene silencing during development. Although PRC2 is a well-established RNA-binding complex, the biological function of PRC2-RNA interaction has been controversial. Here, we study the gene-regulatory role of the inhibitory PRC2-RNA interactions. We report a nuclear long non-coding RNA, LEVER, which mapped 236 kb upstream of the β-globin cluster as confirmed by Nanopore sequencing. LEVER RNA interacts with PRC2 in its nascent form, and this prevents the accumulation of the H3K27 repressive histone marks within LEVER locus. Interestingly, the accessible LEVER chromatin, in turn, suppresses the chromatin interactions between the ε-globin locus and β-globin locus control region (LCR), resulting in a repressive effect on ε-globin gene expression. Our findings validate that the nascent RNA-PRC2 interaction inhibits local PRC2 function in situ. More importantly, we demonstrate that such a local process can in turn regulate the expression of neighboring genes.
    DOI:  https://doi.org/10.1038/s42003-022-03250-x
  21. Nat Commun. 2022 Apr 11. 13(1): 1945
    Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers.
    Renata Bordeira-Carriço, Joana Teixeira, Marta Duque, Mafalda Galhardo, Diogo Ribeiro, Rafael D Acemel, Panos N Firbas, Juan J Tena, Ana Eufrásio, Joana Marques, Fábio J Ferreira, Telmo Freitas, Fátima Carneiro, José Luís Goméz-Skarmeta, José Bessa.
      The pancreas is a central organ for human diseases. Most alleles uncovered by genome-wide association studies of pancreatic dysfunction traits overlap with non-coding sequences of DNA. Many contain epigenetic marks of cis-regulatory elements active in pancreatic cells, suggesting that alterations in these sequences contribute to pancreatic diseases. Animal models greatly help to understand the role of non-coding alterations in disease. However, interspecies identification of equivalent cis-regulatory elements faces fundamental challenges, including lack of sequence conservation. Here we combine epigenetic assays with reporter assays in zebrafish and human pancreatic cells to identify interspecies functionally equivalent cis-regulatory elements, regardless of sequence conservation. Among other potential disease-relevant enhancers, we identify a zebrafish ptf1a distal-enhancer whose deletion causes pancreatic agenesis, a phenotype previously found to be induced by mutations in a distal-enhancer of PTF1A in humans, further supporting the causality of this condition in vivo. This approach helps to uncover interspecies functionally equivalent cis-regulatory elements and their potential role in human disease.
    DOI:  https://doi.org/10.1038/s41467-022-29551-7
  22. Nucleic Acids Res. 2022 Apr 12. pii: gkac238. [Epub ahead of print]
    WashU Epigenome Browser update 2022.
    Daofeng Li, Deepak Purushotham, Jessica K Harrison, Silas Hsu, Xiaoyu Zhuo, Changxu Fan, Shane Liu, Vincent Xu, Samuel Chen, Jason Xu, Shinyi Ouyang, Angela S Wu, Ting Wang.
      WashU Epigenome Browser (https://epigenomegateway.wustl.edu/browser/) is a web-based genomic data exploration tool that provides visualization, integration, and analysis of epigenomic datasets. The newly renovated user interface and functions have enabled researchers to engage with the browser and genomic data more efficiently and effectively since 2018. Here, we introduce a new integrated panel design in the browser that allows users to interact with 1D (genomic features), 2D (such as Hi-C), 3D (genome structure), and 4D (time series) data in a single web page. The browser can display three-dimensional chromatin structures with the 3D viewer module. The 4D tracks, called 'Dynamic' tracks, animatedly display time-series data, allowing for a more striking visual impact to identify the gene or genomic region candidates as a function of time. Genomic data, such as annotation features, numerical values, and chromatin interaction data can all be viewed in the dynamic track mode. Imaging data from microscopy experiments can also be displayed in the browser. In addition to software development, we continue to service and expand the data hubs we host for large consortia including 4DN, Roadmap Epigenomics, TaRGET and ENCODE, among others. Our growing user/developer community developed additional track types as plugins, such as qBed and dynseq tracks, which extend the utility of the browser. The browser serves as a foundation for additional genomics platforms including the WashU Virus Genome Browser (for COVID-19 research) and the Comparative Genome Browser. The WashU Epigenome Browser can also be accessed freely through Amazon Web Services at https://epigenomegateway.org/.
    DOI:  https://doi.org/10.1093/nar/gkac238
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