Department of Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany; Institute of Experimental Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
Department of Cardiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
J Mol Cell Cardiol. 2022 Jan;162:119-129. doi: 10.1016/j.yjmcc.2021.09.001. Epub 2021 Sep 4.
Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a 'repressive' to an 'active' status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes ('first hit') plus a 'second hit' (e.g., exercise) determines the transcriptional response.
组蛋白去乙酰化酶 4（HDAC4）是 IIa 类组蛋白去乙酰化酶（class IIa HDACs）的成员，被认为具有较低的固有去乙酰化酶活性。然而，HDAC4 足以抑制不同的转录因子（TFs），如肌细胞增强因子 2（MEF2）。HDAC4 的转录抑制作用被认为是通过招募其他染色质修饰酶介导的，如甲基转移酶或 I 类组蛋白去乙酰化酶。然而，这一概念尚未通过无偏方法进行研究。因此，我们使用 HDAC4 缺陷型心肌细胞，通过全基因组方法研究了组蛋白修饰 H3K4me3、H3K9ac、H3K27ac、H3K9me2 和 H3K27me3。我们发现，从“抑制性”到“活性”状态的普遍表观遗传转变，其特征是 H3K4me3、H3K9ac 和 H3K27ac 的增加以及 H3K9me2 和 H3K27me3 的减少。在 HDAC4 缺陷型心肌细胞中，MEF2 结合位点在 H3K9ac 和 H3K4me3 上调的启动子区域中显著过表达。例如，我们鉴定出 Adprhl1 的启动子是 HDAC4 和 MEF2 的新基因组靶标。在存在甲基转移酶 SUV39H1 的情况下，HDAC4 在心肌细胞中的过表达能够抑制 Adprhl1 启动子的转录。在全基因组水平上，H3K9 甲基化的减少不会改变基线表达，但与运动诱导的基因表达有关。我们的结论是，一方面，HDAC4 与激活组蛋白修饰（如 H3K4me3 和 H3K9ac）相关联。另一方面，功能后果需要 H3K9me2 的间接调节。HDAC4 靶基因中的 H3K9 低甲基化（“第一击”）加上“第二击”（例如运动）决定了转录反应。
