Role of Bop in Cardiac Development and Function

BOP 在心脏发育和功能中的作用

• 批准号: 6874501
• 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/6874501
• 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）：先天性心脏病和后天性心脏病分别是儿童和成人非感染性死亡的主要原因。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 编码的 m-Bop 蛋白在发育早期的小鼠和雏鸡的心脏区域和肌节以及胎儿和成年小鼠的心肌和骨骼肌中特异性表达。 m-Bop 蛋白包含 MYND 结构域（在其他蛋白中显示可招募组蛋白脱乙酰酶 (HDAC)）和 S-ET 结构域（在其他蛋白中显示可影响染色质结构，有时通过内在组蛋白甲基转移酶 (HMT) 活性）。 这两种活性都可以通过涉及染色质修饰的表观遗传效应来抑制基因表达。 Bop 的靶向失活导致小鼠在胚胎第 10 天（E10 0）死亡，并且 Bop 缺失胎儿的心脏缺乏右心室并具有异常的心肌细胞分化。 E7 75 Bop 缺失胚胎的心脏原基中转录因子 Hand2 的缺失表明 m-Bop 在导致右心室发育的早期基因表达级联中发挥作用。 m-Bop 由于招募 HDAC 而具有体外抑制活性，并且它与 HDAC 直接或间接发生物理相互作用。 m-Bop 与 skNAC（一种心脏和骨骼肌特异性转录因子）相互作用，并在体外肌生成过程和体内心脏生成过程中与 skNAC 共定位。 m-Bop 还与 MITR（一种肌生成的共抑制因子）和 HRT2（一种心室特异性转录因子）相互作用。 我们计划测试以下假设：1) m-Bop 是心肌细胞发育早期染色质修饰的心脏特异性调节剂，并通过与 DNA 结合蛋白的直接和间接相互作用发挥作用，2) m-Bop 和 skNAC 在体外肌生成和体内心脏发育过程中以生理上有意义的方式相互作用。 具体目标是 1) 明确 m-Bop 的 MYND、SET 和其他结构域促进染色质结构改变和调节转录的机制，以及 2) 确定 m-Bop/skNAC 相互作用的生物学意义以及 skNAC 在心脏发生过程中的作用。 这些研究与先天性心脏病心室发育不全的机制相关。 m-Bop 似乎通过促进组蛋白修饰来特异性影响心脏发育，因此以谱系特异性方式进行染色质重组，使其成为已知以这种方式发挥作用的极少数蛋白质之一。这为拟议研究中要研究的机制提供了更广泛的相关性。