Department of Urology and Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
PLoS One. 2012;7(5):e37647. doi: 10.1371/journal.pone.0037647. Epub 2012 May 22.
Although the significance of lysine modifications of core histones for regulating gene expression is widely appreciated, the mechanisms by which these modifications are incorporated at specific regulatory elements during cellular differentiation remains largely unknown. In our previous studies, we have shown that in developing myoblasts the Msx1 homeoprotein represses gene expression by influencing the modification status of chromatin at its target genes. We now show that genomic binding by Msx1 promotes enrichment of the H3K9me2 mark on repressed target genes via recruitment of G9a histone methyltransferase, the enzyme responsible for catalyzing this histone mark. Interaction of Msx1 with G9a is mediated via the homeodomain and is required for transcriptional repression and regulation of cellular differentiation, as well as enrichment of the H3K9me2 mark in proximity to Msx1 binding sites on repressed target genes in myoblast cells as well as the developing limb. We propose that regulation of chromatin status by Msx1 recruitment of G9a and other histone modifying enzymes to regulatory regions of target genes represents an important means of regulating the gene expression during development.
尽管核心组蛋白赖氨酸修饰在调节基因表达方面的意义已被广泛认识，但这些修饰在细胞分化过程中如何在特定的调控元件中被掺入仍然知之甚少。在我们之前的研究中，我们已经表明，在发育中的成肌细胞中，Msx1 同源蛋白通过影响其靶基因染色质的修饰状态来抑制基因表达。我们现在表明，Msx1 的基因组结合通过募集负责催化这种组蛋白标记的 G9a 组蛋白甲基转移酶，促进受抑制靶基因上 H3K9me2 标记的富集。Msx1 与 G9a 的相互作用通过同源域介导，对于转录抑制和细胞分化的调节，以及在受抑制的靶基因的 Msx1 结合位点附近 H3K9me2 标记的富集都是必需的，在成肌细胞和正在发育的肢体中都是如此。我们提出，Msx1 募集 G9a 和其他组蛋白修饰酶到靶基因的调控区域来调节染色质状态，代表了在发育过程中调节基因表达的一种重要手段。
