title: Down-regulation of EBAF in the heart with ventricular septal defects and its regulation by histone acetyltransferase p300 and transcription factors smad2 and cited2.
abstract: As a NODAL pathway inhibitor, EBAF plays a critical role during mammalian cardiac development. As recent tests that have been conducted on gene-targeted mice indicate, its expression is frequently altered where cardiac defects are present. We aimed to explore the EBAF expression pattern and molecular mechanism of EBAF gene for VSD genesis. In this report, we show that the average expression of EBAF in the disease tissues of VSD patients was lower than the expression in normal fetuses without VSD. Further study showed that the expression pattern of EBAF was potentially involved in cardiomyocyte apoptosis by Annexin-V and RT-PCR assays. We also found that abnormal activation of NODAL-PITX2C pathway was associated with down-regulation of EBAF. By luciferase reporter assays, we find that EBAF expression is mediated by transcriptional factors smad2 and cited2. In addition, ChIP assays showed that histone acetyltransferase p300 is involved in the activation of EBAF through inducing hyperacetylation of histone H4 at the EBAF promoter. Co-immunoprecipitation also indicates that the expression of EBAF is regulated by a transcriptional complex including p300, smad2, and cited2. This study revealed a novel regulator mechanism of EBAF, which may be a potential molecular target for halting the onset of VSDs. They also indicate that smad2, cited2, and p300 may play important roles in modulating the confirmation of ventricular septal defects.
authors.affiliation: Department of Genetics, National Research Institute for Family Planning, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Su
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Lina
authors.initials: L
authors.lastname: Guan
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Gao
authors.forename: Huiling
authors.initials: H
authors.lastname: Zhang
authors.forename: E
authors.initials: E
authors.lastname: Dandan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D006345:Heart Septal Defects, Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D055458:Left-Right Determination Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097577:Homeobox Protein PITX2
chemical_list: D050881:E1A-Associated p300 Protein; D006657:Histones; D018398:Homeodomain Proteins; D055458:Left-Right Determination Factors; D055457:Nodal Protein; D012333:RNA, Messenger; D012097:Repressor Proteins; D051899:Smad2 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C486381:CITED2 protein, human; C411603:LEFTY2 protein, human; C526007:NODAL protein, human; C497782:SMAD2 protein, human; C494360:EP300 protein, human
keywords: EBAF; cited2; p300; smad2