Probing the Function of Metazoan Histones with a Systematic Library of H3 and H4 Mutants

Zhang, Weimin; Zhang, Xuedi; Xue, Zhaoyu; Li, Yijie; Ma, Qing; Ren, Xiangle; Zhang, Jiaying; Yang, Shenghao; Yang, Lijuan; Wu, Menghua; Ren, Menda; Xi, Rongwen; Liu, Ji‐Long; Matunis, Erika; Dai, Junbiao; Gao, Guanjun

doi:10.2139/ssrn.3188494

Cited by 16 publications

(24 citation statements)

References 68 publications

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“…A possible explanation for the poorer survival of H3 K36R mutants in the strain generated here could be that histone transgene expression from the 3xHisGU H3K36R miniarrays is for some reason less effective that in the case of the 12x HisGU H3K36R array. We also note that a recent study reported that among Df(2L)HisC homozygotes that carry 20 HisGU H3K36A copies, about 50% of the mutant animals develop up to the pupal stages ( Zhang et al, 2019 ). Zhang et al have not analyzed their H3 K36A mutants any further but it is possible that the higher copy number of the HisGU H3K36A cassette accounts for the better survival compared to the H3 K36A strain generated in this study.…”

Section: Methodssupporting

confidence: 53%

Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

Finogenova

Bonnet

Poepsel

et al. 2020

eLife

114

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Repression of genes by Polycomb requires that PRC2 modifies their chromatin by trimethylating lysine 27 on histone H3 (H3K27me3). At transcriptionally active genes, di- and trimethylated H3K36 inhibit PRC2. Here, the cryo-EM structure of PRC2 on dinucleosomes reveals how binding of its catalytic subunit EZH2 to nucleosomal DNA orients the H3 N-terminus via an extended network of interactions to place H3K27 into the active site. Unmodified H3K36 occupies a critical position in the EZH2-DNA interface. Mutation of H3K36 to arginine or alanine inhibits H3K27 methylation by PRC2 on nucleosomes in vitro. Accordingly, Drosophila H3K36A and H3K36R mutants show reduced levels of H3K27me3 and defective Polycomb repression of HOX genes. The relay of interactions between EZH2, the nucleosomal DNA and the H3 N-terminus therefore creates the geometry that permits allosteric inhibition of PRC2 by methylated H3K36 in transcriptionally active chromatin.

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Section: Methodssupporting

confidence: 53%

Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

Finogenova

Bonnet

Poepsel

et al. 2020

eLife

114

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“…Chromatin components, including core histones, are loaded in vast excess of what is required for the first divisions (Horard and Loppin, 2015;Adamson and Woodland, 1974;Woodland and Adamson, 1977;Shindo and Amodeo, 2019). In Drosophila, maternal histone stores are sufficient for progression through the MBT, but zygotic histone production is required for progression past the first post-MBT cell cycle (Günesdogan et al, 2010(Günesdogan et al, , 2014Zhang et al, 2018). It has been suggested that overabundant histones compete with transcription factors for DNA binding to repress transcription in the early cycles (Almouzni et al, 1990(Almouzni et al, , 1991Prioleau et al, 1994;Almouzni and Wolffe, 1995;Amodeo et al, 2015;Joseph et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Histone concentration regulates the cell cycle and transcription in early development

et al. 2019

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The early embryos of many animals, including flies, fish and frogs, have unusually rapid cell cycles and delayed onset of transcription. These divisions are dependent on maternally supplied RNAs and proteins including histones. Previous work suggests that the pool size of maternally provided histones can alter the timing of zygotic genome activation (ZGA) in frogs and fish. Here, we examine the effects of under-and overexpression of maternal histones in Drosophila embryogenesis. Decreasing histone concentration advances zygotic transcription, cell cycle elongation, Chk1 activation and gastrulation. Conversely, increasing histone concentration delays transcription and results in an additional nuclear cycle before gastrulation. Numerous zygotic transcripts are sensitive to histone concentration, and the promoters of histone-sensitive genes are associated with specific chromatin features linked to increased histone turnover. These include enrichment of the pioneer transcription factor Zelda, and lack of SIN3A and associated histone deacetylases. Our findings uncover a crucial regulatory role for histone concentrations in ZGA of Drosophila.

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“…Drosophila melanogaster, a genetically tractable organism with a well characterized developmental program, has contributed significantly to our understanding of the functions of H1 (for reviews see Hergeth and Schneider 2015;and Bayona-Feliu et al 2016). Drosophila his1 gene exists in a multi-copy gene cluster at the histone locus, similar to the situation in other higher eukaryotes, therefore genetic knock-out of his1 has not been utilized for the dissection of H1 function even though recent advances in genome engineering has made it possible (Günesdogan et al 2010;McKay et al 2015;Zhang et al 2019). Instead, prior functional studies of H1 relies on RNAi knock-down or overexpression approaches.…”

Section: Introductionmentioning

confidence: 99%

Compensatory replacement of the BigH1 variant histone by canonical H1 supports normal embryonic development in Drosophila

Han

Chen

et al. 2019

Preprint

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Histone variants carry specific functions in addition to those fulfilled by their canonical counterparts. Variants of the linker Histone H1 are prevalent in vertebrates and based on the pattern of their expression, many are presumed to function during germline and the earliest zygotic stages of development.While the existence of multiple H1 variants has hampered their study in vertebrates, a single variant, BigH1, was identified in Drosophila, promising to accelerate our understanding of the biological functions of H1 and H1 variants.Here we uncovered evidence for a compensatory activity that loads maternal H1 onto BigH1-devoid chromatin. Remarkably, this H1-based chromatin state is fully functional in supporting normal embryonic development, suggesting that H1 carries the essential function of the BigH1 molecule under the same developmental context. In addition, we discovered that this compensatory replacement of BigH1 with H1 might be limited to rapidly cycling cells in early embryos.

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Probing the Function of Metazoan Histones with a Systematic Library of H3 and H4 Mutants

Cited by 16 publications

References 68 publications

Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3

Histone concentration regulates the cell cycle and transcription in early development

Compensatory replacement of the BigH1 variant histone by canonical H1 supports normal embryonic development in Drosophila

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