Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver.

Post-translational modifications of histone tails play a crucial role in gene regulation. Here, we performed chromatin profiling by quantitative targeted mass spectrometry to assess all possible modifications of the core histones. We discovered a novel bivalent combination, a dually-marked H3K9me3/H3K14ac modification in the liver, that is significantly decreased in old hepatocytes. Subsequent genome-wide location analysis (ChIP-Seq) identified 1032 and 668 bivalent regions in young and old livers, respectively, with 280 in common. Histone H3K9 deacetylase Hdac3, as well as H3K9 methyltransferase Setdb1, found in complex Kap1, occupied bivalent regions in both young and old livers, correlating to presence of H3K9me3. Expression of genes associated with bivalent regions in young liver, including those regulating cholesterol secretion and triglyceride synthesis, is upregulated in old liver once the bivalency is lost. Hence, H3K9me3/H3K14ac dually-marked regions define a poised inactive state that is resolved with loss of one or both of the chromatin marks, which subsequently leads to change in gene expression.

组蛋白尾的翻译后修饰在基因调控中发挥关键作用。本研究通过定量靶向质谱法开展染色质谱分析，以评估核心组蛋白的所有潜在修饰类型。我们在肝脏组织中发现了一种全新的二价修饰组合：双标记的H3K9me3/H3K14ac修饰，该修饰在衰老肝细胞中显著下调。后续的全基因组定位分析（ChIP-Seq）分别在年轻与衰老肝脏样本中鉴定出1032个和668个二价区域，其中280个区域为两者共有。组蛋白H3K9去乙酰化酶Hdac3，以及位于Kap1复合物中的组蛋白H3K9甲基转移酶Setdb1，均可结合年轻与衰老肝脏中的二价区域，该结合与H3K9me3修饰的存在呈正相关。年轻肝脏中二价区域关联的基因（包括调控胆固醇分泌与甘油三酯合成的基因），在二价状态丧失后，于衰老肝脏中出现表达上调。综上，H3K9me3/H3K14ac双标记区域定义了一种预备失活状态，该状态会随着一个或两个染色质标记的丢失而被解除，进而引发基因表达的改变。