Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis

Mech Dev. 2013 Nov-Dec;130(11-12):519-31. doi: 10.1016/j.mod.2013.07.002. Epub 2013 Jul 24.

Abstract

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.

Keywords: Atrioventricular cushion; Atrioventricular septal defects; Cardiogenesis; Gene repression; Histone H3 lysine 9 methyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Septum / embryology
  • Atrial Septum / enzymology*
  • Atrial Septum / pathology
  • Embryo, Mammalian
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Genetic Engineering
  • Heart Septal Defects / embryology
  • Heart Septal Defects / enzymology
  • Heart Septal Defects / genetics*
  • Heart Septal Defects / pathology
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics*
  • Histones / metabolism
  • Homologous Recombination
  • Male
  • Mice
  • Mice, Transgenic
  • Morphogenesis / genetics*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Signal Transduction

Substances

  • Histones
  • G9a protein, mouse
  • GLP protein, mouse
  • Histone-Lysine N-Methyltransferase

Supplementary concepts

  • Atrioventricular Septal Defect