Institute of Molecular Biology of Barcelona, IBMB, CSIC, Baldiri Reixac, 4, 08028 Barcelona, Spain.
Institute for Research in Biomedicine, IRB Barcelona. The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.
Nucleic Acids Res. 2020 May 7;48(8):4147-4160. doi: 10.1093/nar/gkaa122.
Linker histones H1 are principal chromatin components, whose contribution to the epigenetic regulation of chromatin structure and function is not fully understood. In metazoa, specific linker histones are expressed in the germline, with female-specific H1s being normally retained in the early-embryo. Embryonic H1s are present while the zygotic genome is transcriptionally silent and they are replaced by somatic variants upon activation, suggesting a contribution to transcriptional silencing. Here we directly address this question by ectopically expressing dBigH1 in Drosophila S2 cells, which lack dBigH1. We show that dBigH1 binds across chromatin, replaces somatic dH1 and reduces nucleosome repeat length (NRL). Concomitantly, dBigH1 expression down-regulates gene expression by impairing RNApol II binding and histone acetylation. These effects depend on the acidic N-terminal ED-domain of dBigH1 since a truncated form lacking this domain binds across chromatin and replaces dH1 like full-length dBigH1, but it does not affect NRL either transcription. In vitro reconstitution experiments using Drosophila preblastodermic embryo extracts corroborate these results. Altogether these results suggest that the negatively charged N-terminal tail of dBigH1 alters the functional state of active chromatin compromising transcription.
连接组蛋白 H1 是主要的染色质成分,但其在染色质结构和功能的表观遗传调控中的作用尚不完全清楚。在后生动物中,特定的连接组蛋白在生殖细胞中表达,雌性特异性的 H1 通常在早期胚胎中保留。胚胎 H1 在合子基因组转录沉默时存在,并且在激活时被体细胞变体取代,这表明其对转录沉默有贡献。在这里,我们通过在缺乏 dBigH1 的 Drosophila S2 细胞中外源表达 dBigH1 来直接解决这个问题。我们表明 dBigH1 可以跨越染色质结合,取代体细胞 dH1 并降低核小体重复长度 (NRL)。同时,dBigH1 的表达通过损害 RNApol II 结合和组蛋白乙酰化来下调基因表达。这些效应依赖于 dBigH1 的酸性 N 端 ED 结构域,因为缺乏该结构域的截断形式可以像全长 dBigH1 一样跨越染色质结合并取代 dH1,但它既不影响 NRL 也不影响转录。使用果蝇胚前胚提取液进行的体外重建实验验证了这些结果。总之,这些结果表明 dBigH1 的带负电荷的 N 端尾巴改变了活性染色质的功能状态,从而影响转录。