English David M, Lee Samuel N, Sabat Khadija A, Baker India M, Pham Trong Khoa, Collins Mark O, Cowley Shaun M
Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, LE1 7RH, United Kingdom.
Cambridge Stem Cell Institute & Department of Haematology, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, United Kingdom.
Nucleic Acids Res. 2025 Feb 8;53(4). doi: 10.1093/nar/gkae1223.
Histone Deacetylase 1 (HDAC1) removes acetyl groups from lysine residues on core histones, a critical step in regulating chromatin accessibility. Despite histone deacetylation being an apparently repressive activity, suppression of HDACs causes both up- and downregulation of gene expression. Here we exploited the degradation tag (dTAG) system to rapidly degrade HDAC1 in mouse embryonic stem cells (ESCs) lacking its paralog, HDAC2. The dTAG system allowed specific degradation and removal of HDAC1 in <1 h (100x faster than genetic knockouts). This rapid degradation caused increased histone acetylation in as little as 2 h, with H2BK5 and H2BK11 being the most sensitive. The majority of differentially expressed genes following 2 h of HDAC1 degradation were upregulated (275 genes up versus 15 down) with increased proportions of downregulated genes observed at 6 h (1153 up versus 443 down) and 24 h (1146 up versus 967 down), respectively. Upregulated genes showed increased H2BK5ac and H3K27ac around their transcriptional start site (TSS). In contrast, decreased acetylation and chromatin accessibility of super-enhancers was linked to the most strongly downregulated genes. These findings suggest a paradoxical role for HDAC1 in the maintenance of histone acetylation levels at critical enhancer regions required for the pluripotency-associated gene network.
组蛋白去乙酰化酶1（HDAC1）从核心组蛋白的赖氨酸残基上去除乙酰基，这是调节染色质可及性的关键步骤。尽管组蛋白去乙酰化显然是一种抑制性活动，但抑制HDAC会导致基因表达的上调和下调。在这里，我们利用降解标签（dTAG）系统在缺乏其旁系同源物HDAC2的小鼠胚胎干细胞（ESC）中快速降解HDAC1。dTAG系统允许在不到1小时内特异性降解和去除HDAC1（比基因敲除快100倍）。这种快速降解在短短2小时内就导致组蛋白乙酰化增加，其中H2BK5和H2BK11最为敏感。HDAC1降解2小时后，大多数差异表达基因上调（275个基因上调对15个基因下调），在6小时（1153个基因上调对443个基因下调）和24小时（1146个基因上调对967个基因下调）分别观察到下调基因比例增加。上调基因在其转录起始位点（TSS）周围显示H2BK5ac和H3K27ac增加。相反，超级增强子的乙酰化降低和染色质可及性与下调最强烈的基因有关。这些发现表明，HDAC1在维持多能性相关基因网络所需的关键增强子区域的组蛋白乙酰化水平方面具有矛盾的作用。
