Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan.
Mech Dev. 2013 Nov-Dec;130(11-12):519-31. doi: 10.1016/j.mod.2013.07.002. Epub 2013 Jul 24.
Lysine methylation of the histone tail is involved in a variety of biological events. G9a and GLP are known as major H3-K9 methyltransferases and contribute to transcriptional silencing. The functions of these genes in organogenesis remain largely unknown. Here, we analyzed the phenotypes of cardiomyocyte specific GLP knockout and G9a knockdown (GLP-KO/G9a-KD) mice. The H3-K9 di-methylation level decreased markedly in the nuclei of the cardiomyocytes of GLP-KO/G9a-KD mice, but not single G9a or GLP knockout mice. In addition, GLP-KO/G9a-KD mice showed neonatal lethality and severe cardiac defects (atrioventricular septal defects, AVSD). We also showed that hypoplasia in the atrioventricular cushion, which is a main part of the atrioventricular septum, caused AVSD. Expression analysis revealed downregulation of 2 AVSD related genes and upregulation of several non-cardiac specific genes in the hearts of GLP-KO/G9a-KD mice. These data indicate that G9a and GLP are required for sufficient H3-K9 di-methylation in cardiomyocytes and regulation of expression levels in multiple genes. Moreover, our findings show that G9a and GLP have an essential role in normal morphogenesis of the atrioventricular septum through regulation of the size of the atrioventricular cushion.
组蛋白尾部赖氨酸甲基化参与多种生物学事件。G9a 和 GLP 被认为是主要的 H3-K9 甲基转移酶，有助于转录沉默。这些基因在器官发生中的功能在很大程度上仍然未知。在这里，我们分析了心肌细胞特异性 GLP 敲除和 G9a 敲低（GLP-KO/G9a-KD）小鼠的表型。GLP-KO/G9a-KD 小鼠心肌细胞的 H3-K9 二甲基化水平明显降低，但单敲除 G9a 或 GLP 的小鼠则没有。此外，GLP-KO/G9a-KD 小鼠表现出新生儿致死性和严重的心脏缺陷（房室间隔缺损，AVSD）。我们还表明，房室间隔瓣的发育不良是 AVSD 的主要原因，房室间隔瓣是房室间隔的主要部分。表达分析显示，GLP-KO/G9a-KD 小鼠心脏中 2 个与 AVSD 相关的基因下调，多个非心脏特异性基因上调。这些数据表明，G9a 和 GLP 是心肌细胞中 H3-K9 二甲基化所必需的，并且可以调节多个基因的表达水平。此外，我们的研究结果表明，G9a 和 GLP 通过调节房室间隔瓣的大小，在房室间隔的正常形态发生中发挥重要作用。
