title: Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes.
abstract: Differentiation of embryonic stem (ES) cells into cardiac myocytes requires activation of a cardiac-specific gene program. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) govern gene expression patterns by being recruited to target genes through association with specific transcription factors. One of the HATs, p300, serves as a coactivator of cardiac-specific transcription factors such as GATA-4. The HAT activity of p300 is required for acetylation and DNA binding of GATA-4 and its full transcriptional activity as well as for promotion of a transcriptionally active chromatin configuration. However, the roles of HATs and HDACs in post-translational modification of GATA-4 during the differentiation of ES cells into cardiac myocytes remain unknown. In an ES cell model of developing embryoid bodies, an acetylated form of GATA-4 and its DNA binding increased concomitantly with the expression of p300 during the differentiation of ES cells into cardiac myocytes. Treatment of ES cells with trichostatin A (TSA), a specific HDAC inhibitor, induced acetylation of histone-3/4 near GATA sites within the atrial natriuretic factor promoter. In addition, TSA augmented the increase in an acetylated form of GATA-4 and its DNA binding during the ES cell differentiation. Finally, TSA facilitated the expression of green fluorescence protein under the control of the cardiac-specific Nkx-2.5 promoter and of endogenous cardiac beta-myosin heavy chain during the differentiation. These findings demonstrate that acetylation of GATA-4 as well as of histones is involved in the differentiation of ES cells into cardiac myocytes.
authors.affiliation: Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Kawamura
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Morimoto
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wada
authors.forename: Maretoshi
authors.initials: M
authors.lastname: Hirai
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hidaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Koji
authors.initials: K
authors.lastname: Hasegawa
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050881:E1A-Associated p300 Protein; D050991:GATA4 Transcription Factor; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D006657:Histones; D006877:Hydroxamic Acids; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C012589:trichostatin A; D004247:DNA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse