Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 1HH, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 1HH, UK.
Nat Commun. 2023 Nov 9;14(1):7243. doi: 10.1038/s41467-023-43115-3.
Histone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where combinations of modifications specify unique downstream functions, is widely accepted and can be demonstrated in vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognize trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me2/3 during mitosis. We find that H3T3ph anti-correlates with adjacent H3K4me2/3 in cells, and that the PHD domain of TAF3 can bind H3K4me2/3 in isolated mitotic chromatin despite the presence of H3T3ph. Unlike in vitro, H3K4 readers are still displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.
组蛋白修饰影响 reader 蛋白在染色体上的募集,从而调节转录和细胞分裂等事件。组蛋白密码的概念,即修饰的组合指定独特的下游功能,已被广泛接受,并可以在体外得到证明。例如,在合成肽上,组蛋白 H3 丝氨酸-3(H3T3ph)的磷酸化可阻止识别相邻赖氨酸-4(H3K4me3)三甲基化的 reader 蛋白的结合,包括 TFIID 的 TAF3 成分。为了在细胞中研究这些组合效应,我们分析了有丝分裂过程中 H3T3ph 和 H3K4me2/3 的全基因组分布。我们发现,在细胞中,H3T3ph 与相邻的 H3K4me2/3 呈负相关,并且尽管存在 H3T3ph,TAF3 的 PHD 结构域仍可以在分离的有丝分裂染色质中结合 H3K4me2/3。与体外不同,在缺乏 H3T3ph 的 Haspin 耗尽细胞中,H3K4 阅读器在有丝分裂期间仍从染色体上置换。因此,H3T3ph 不太可能是细胞分裂过程中转录下调的原因。