Role of Bop in Cardiac Development and Function

BOP 在心脏发育和功能中的作用

• 批准号: 6744117
• 负责人: HALEY O TUCKER
• 金额: $ 37.6万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744117
• 关键词: DNA binding protein; amidohydrolases; cardiogenesis; chromatin; congenital heart disorder; developmental genetics; enzyme activity; gene deletion mutation; gene induction /repression; genetically modified animals; histones; laboratory mouse; mammalian embryology; methyltransferase; myogenesis; protein protein interaction; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Congenital heart disease and acquired heart disease are the leading non-infectious causes of death in children and adults, respectively. The long term objectives of this project are to understand the role of m-Bop proteins in cardiac myocyte differentiation and cardiac development. Bop encodes m-Bop proteins specifically expressed in the heart field and myotome of the mouse and chick early in development as well as in fetal and adult mouse myocardium and skeletal muscle. m-Bop proteins contain both a MYND domain, shown in other proteins to recruit histone deacetylases (HDACs), and a S-ET domain, shown elsewhere to affect chromatin structure, sometimes through intrinsic histone methyltransferase (HMT) activity. Both activities can repress gene expression through epigenetic effects involving chromatin modifications. Targeted inactivation of Bop in mice leads to death at embryonic day 10 (El0 0), and hearts of Bop-null fetuses lack a right ventricle and have abnormal cardiomyocyte differentiation. Absence of the transcription factor, Hand2, from the heart primordia of E7 75 Bop-null embryos suggests a role for m-Bop in an early gene expression cascade that leads to right ventricular development. m-Bop has repressive activity in vitro due to recruitment of HDACs, and it physically interacts directly or indirectly with HDACs. m-Bop interacts with skNAC, a heart- and skeletal muscle-specific transcription factor, and co-localizes with skNAC during myogenesis in vitro and during cardiogenesis in vivo. m-Bop also interacts with MITR, a co-repressor of myogenesis, and HRT2, a heart ventricle-specific transcription factor. We plan to test the hypotheses that 1) m-Bop is a cardiac-specific regulator of chromatin modifications early in cardiomyocyte development and functions through direct and indirect interactions with DNA-binding proteins, and 2) that m-Bop and skNAC interact in a physiologically meaningful manner during myogenesis in vitro and cardiac development in vivo. Specific Aims are 1) To define the mechanisms by which the MYND, SET and other domains of m-Bop promote alterations in chromatin structure and regulate transcription, and 2) To determine the biological significance of m-Bop/skNAC interaction and the role of skNAC during cardiogenesis. These studies are relevant to mechanisms that may underlie ventricular hypoplasia in congenital heart disease. That m-Bop appears to specifically affect heart development by promoting histone modifications and hence chromatin reorganization in a lineage-specific fashion places it among a very few proteins known to operate in this way. This gives a broader relevance to the mechanisms to be investigated in the proposed studies.

描述（由申请人提供）：先天性心脏病和心脏病分别是儿童和成人的主要非感染死亡原因。该项目的长期目标是了解M-BOP蛋白在心肌细胞分化和心脏发育中的作用。 BOP编码在发育早期以及胎儿和成年小鼠心肌和骨骼肌中，在心脏场和小鼠和小鸡的心脏和小鸡的近视体中编码M-BOP蛋白。 M-BOP蛋白既包含一个MyND结构域，在其他蛋白中显示为募集组蛋白脱乙酰基酶（HDACS）和S-ET结构域，在其他地方显示以影响染色质结构，有时还通过固有的组蛋白甲基转移酶（HMT）活性。 两种活动都可以通过涉及染色质修饰的表观遗传作用来抑制基因表达。小鼠中BOP的靶向失活导致胚胎第10天（EL0 0）死亡，而Bop-Null胎儿的心脏缺乏右心室，并且具有异常的心肌细胞分化。 E7 75 BOP-NULL胚胎的心脏原始中没有转录因子Hand2，这表明M-BOP在早期基因表达级联反应中起作用，从而导致右心室发育。 M-BOP由于HDAC的募集而在体外具有抑郁活性，并且与HDAC直接或间接地相互作用。 M-BOP与SKNAC（心脏和骨骼肌特异性转录因子）相互作用，并在体外和心脏发生期间与SKNAC共定位。 M-BOP还与肌发生的共抑制剂Mitr和HRT2（心心室特异性转录因子）相互作用。 我们计划测试1）M-BOP是心肌细胞开发和功能早期的心脏特异性调节剂，通过与DNA结合蛋白的直接和间接相互作用以及2）M-BOP和SKNAC在生理上有意义的方式中在VITRO和CardCardiac开发过程中具有有意义的有意义的方式。 具体目的是1）定义MYND，SET和其他M-BOP促进染色质结构的改变并调节转录的机制，以及2）确定M-BOP/SKNAC相互作用的生物学意义以及SKNAC在心脏病生成中的作用。 这些研究与可能基于先天性心脏病中心室发育不全的机制有关。 M-BOP似乎通过促进组蛋白的修饰并因此在谱系特异性时尚中促进染色质的重组会特别影响心脏发育，将其构成以这种方式运作的极少数蛋白质。这给出了与拟议的研究中要研究的机制更广泛的相关性。