title: Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis.
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.
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences, Machida 194-8511, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Inagawa
authors.forename: Kuniko
authors.initials: K
authors.lastname: Nakajima
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Makino
authors.forename: Satoko
authors.initials: S
authors.lastname: Ogawa
authors.forename: Mizuyo
authors.initials: M
authors.lastname: Kojima
authors.forename: Satomi
authors.initials: S
authors.lastname: Ito
authors.forename: Aiko
authors.initials: A
authors.lastname: Ikenishi
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hayashi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Kazuomi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Obayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Tachibana
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shinkai
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maeda
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyagawa-Tomita
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D054087:Atrial Septum / Q000196:embryology / Q000201:enzymology* / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D005818:Genetic Engineering; D006343:Heart Septal Defects / Q000196:embryology / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D059765:Homologous Recombination; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction
chemical_list: D006657:Histones; C533711:G9a protein, mouse; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: Atrioventricular cushion; Atrioventricular septal defects; Cardiogenesis; Gene repression; Histone H3 lysine 9 methyltransferase