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Nucleosomal Asymmetry Shapes Histone Mark Binding And bioRxiv preprint doi: https://doi.org/10.1101/2021.02.08.430127; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Nucleosomal Asymmetry Shapes Histone Mark Binding 2 and Promotes Poising at Bivalent Domains 3 4 5 6 1 1¶ 1¶ 1¶ 7 Elana Bryan , Marie Warburton , Kimberly M. Webb , Katy A. McLaughlin , 1 3 1 3 8 Christos Spanos , Christina Ambrosi , Viktoria Major , Tuncay Baubec , Juri 1,2 1* 9 Rappsilber , Philipp Voigt 10 11 12 1 13 Wellcome Centre for Cell Biology, School of Biological Sciences, University of 14 Edinburgh, Edinburgh EH9 3BF, United Kingdom. 2 15 Chair of Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, 16 13355 Berlin, Germany. 3 17 Department of Molecular Mechanism of Disease, University of Zurich, CH- 18 8057 Zurich, Switzerland 19 20 ¶ 21 These authors contributed equally. 22 23 24 25 * Correspondence should be addressed to P.V.: [email protected] 26 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.08.430127; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 27 Summary 28 29 Promoters of developmental genes in embryonic stem cells (ESCs) are marked by 30 histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric 31 nucleosomal conformation, with each sister histone H3 carrying only one mark. These 32 bivalent domains are thought to poise genes for timely activation upon differentiation. 33 Here we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 34 binders but fail to enrich activating H3K4me3 binders, despite presence of H3K4me3, 35 thereby promoting a poised state. Strikingly, the bivalent mark combination further 36 attracts chromatin proteins that are not recruited by each mark individually, including 37 the histone acetyltransferase complex KAT6B (MORF). Knockout of KAT6B blocks 38 neuronal differentiation, demonstrating that bivalency-specific readers are critical for 39 proper ESC differentiation. These findings reveal how histone mark bivalency directly 40 promotes establishment of a poised state at developmental genes, while highlighting 41 how nucleosomal asymmetry is critical for histone mark readout and function. 42 43 44 45 46 Keywords: Chromatin, transcription, histone methylation, histone acetylation, bivalent 47 domains, embryonic stem cells, differentiation, Polycomb. 48 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.08.430127; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 49 Introduction 50 51 Histone modifications have emerged as key regulators of transcription and other 52 chromatin-templated processes. Often in combinatorial fashion, histone marks set up 53 chromatin environments that reflect, reinforce, and potentially instruct transcriptional 54 states by directly regulating access to the DNA or by recruiting factors that activate or 55 repress transcription. Promoters of developmental genes in embryonic stem cells 56 (ESCs) are marked by a distinctive histone modification signature comprised of the 57 active histone mark histone H3 lysine 4 trimethylation (H3K4me3) and the repressive 58 mark H3K27me3 (Azuara et al., 2006; Bernstein et al., 2006; Harikumar and Meshorer, 59 2015; Mikkelsen et al., 2007; Voigt et al., 2013). These so-called ‘bivalent domains’ 60 are presumed to poise expression of developmental genes primarily in ESCs by 61 maintaining a repressed but plastic state that allows for prompt activation or stable 62 repression of these genes upon differentiation cues. Bivalent domains are established 63 by the histone methyltransferase complexes MLL2 and Polycomb repressive complex 64 (PRC) 2, catalyzing H3K4me3 and H3K27me3, respectively (Christophersen and 65 Helin, 2010; Piunti and Shilatifard, 2016; Schuettengruber et al., 2017; Yu et al., 2019). 66 Supporting a pivotal role of bivalent domains in regulating developmental genes, 67 knockouts or loss-of-function mutations in these complexes abolish bivalency and lead 68 to developmental defects in mice and compromised differentiation potential in ESCs 69 (Laugesen and Helin, 2014; Piunti and Shilatifard, 2016; Vastenhouw and Schier, 70 2012). However, the mechanisms by which bivalent domains poise genes for 71 expression are largely unclear and it remains elusive whether the bivalent histone 72 marks themselves are key drivers of poising. 73 Given the central role of binding proteins or ‘readers’ in executing histone mark 74 function, proteins that bind H3K4me3 or H3K27me3 are candidates for translating 75 bivalency into a poised state via a histone mark-based mechanism. Complexes 76 featuring binding proteins for the active H3K4me3 mark comprise the general 77 transcription factor TFIID, transcriptional co-activators, histone modifiers, and 78 chromatin remodelers, whereas the repressive H3K27me3 mark is primarily 79 recognized by PRC2 and canonical PRC1 complexes (Bartke et al., 2010; Eberl et al., 80 2013; Musselman et al., 2012; Taverna et al., 2007; Vermeulen et al., 2010). However, 81 thus far recognition of H3K4me3 and H3K27me3 has only been studied individually, 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.08.430127; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 82 rendering potential antagonistic or multivalent synergistic effects of their bivalent 83 coexistence elusive. Moreover, we and others have shown that bivalent nucleosomes 84 are asymmetrically modified, carrying H3K4me3 and H3K27me3 on two separate 85 histone H3 copies, rather than featuring two histone H3 copies modified with both 86 H3K4me3 and H3K27me3 (Shema et al., 2016; Voigt et al., 2012). However, it remains 87 unclear how nucleosomal asymmetry affects recruitment of histone mark binding 88 proteins—and thus histone mark function—at bivalent nucleosomes and beyond. 89 Here, we set out to determine how asymmetric bivalent nucleosomes are decoded 90 in order to clarify whether the bivalent marks directly act to poise developmental genes 91 in ESCs. Using an approach based on nucleosome pulldown assays with 92 recombinant, site-specifically modified nucleosomes followed by quantitative mass 93 spectrometry (MS) analysis, we reveal that bivalent nucleosomes recruit repressive 94 complexes as well as bivalency-specific binders, but fail to recruit H3K4me3 binders. 95 These findings provide evidence for a histone mark-based poising mechanism and 96 illustrate how nucleosomal asymmetry regulates histone mark function. 97 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.02.08.430127; this version posted February 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 98 Results 99 100 Monovalent asymmetric nucleosomes fail to recruit H3K4me3 and H3K27me3 101 binding proteins 102 In order to resolve how the asymmetric bivalent mark combination might directly 103 establish or facilitate poising at bivalent domains, we generated site-specifically 104 modified histones via native chemical ligation and assembled them into recombinant 105 nucleosomes carrying symmetric and asymmetric H3K4me3 and H3K27me3 106 (Figure S1). We then carried out nucleosome pulldown assays with mouse E14 ESC 107 nuclear extract (NE) followed by label-free quantification (LFQ) liquid chromatography 108 (LC)-coupled mass spectrometry (MS) analysis (Figure 1A). We first sought to 109 determine how asymmetric monovalent presence of H3K4me3—as observed at 110 bivalent domains in vivo—regulates its readout and affects recruitment of H3K4me3 111 binding proteins. As expected from previous studies (Bartke et al., 2010; Eberl et al., 112 2013), when performing pulldowns with symmetric H3K4me3 (denoted as 113 H3K4me3/3) nucleosomes, we observed specific enrichment of a host of known 114 H3K4me3 binding proteins, including members of the TFIID, SETD1, and SIN3A/B 115 complexes, chromatin remodelers such as NURF, CHD1, and CHD8, and other PHD 116 finger proteins such as PHF2 (Figures 1B and 1C, Table S1). We further observed 117 depletion of HMG20B, PHF21A, G9a/GLP, and PRC2 on H3K4me3/3 nucleosomes 118 (Figures 1B and 1C, Table S1). Strikingly, when we performed analogous pulldown 119 experiments with asymmetric (‘H3K4me0/3’) nucleosomes, enrichment of H3K4me3 120 binders and depletion of repressive factors was lost (Figures 1B and 1C, Table S1), 121 indicating that asymmetric nucleosomes fail to recruit H3K4me3 binding proteins, 122 despite presence of the mark on one of the two histone H3 copies in the nucleosome. 123 In line with these findings, asymmetric H3K27me3 nucleosomes likewise failed to 124 enrich known H3K27me3 binding proteins, while symmetric H3K27me3 nucleosomes 125 robustly recruited known H3K27me3 binders (Figures 1B and 1D, Table S2). Taken 126 together, symmetric modification appears to be required to achieve enrichment of 127 binding proteins for both H3K4me3 and H3K27me3 in nucleosome pulldown assays, 128 while recruitment was diminished for asymmetric nucleosomes.
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