Integrated Analysis: Epigenetic Regulation of Gene Expression During Orofacial De

描述（由申请人提供）：本提案的长期目标是阐明哺乳动物口面发育过程中基因表达的表观遗传调控作用。哺乳动物口面部组织的形成是一个多方面的、同步的发育过程，涉及细胞迁移、增殖、分化、凋亡和细胞外基质的合成。所有这些关键的细胞过程都是在一个 编码生长和分化因子、信号传导介质、转录因子和细胞外基质蛋白的多种基因，其表达依次由表观遗传学调节的调控元件控制。这些过程中的任何一个中断都可能导致口面裂。新出现的证据强烈支持的重要性，表观遗传机制控制的关键基因的表达口面个体发育的关键。我们实验室最近的研究表明，在胚胎口面组织中发生了精确的差异基因甲基化和表达模式。初步数据显示，几个表观遗传调控的基因，记录在orofacial形态发生的关键作用。因此，我们建议测试的假设，通过差异甲基化区域的差异表达基因的调节，是必要的胚胎orofacial地区的正常发展。本研究的主要目的是：1）在口面发育过程中，差异表达的mRNA基因受到表观遗传学的调控。2)差异表达和表观遗传学调节的基因转录物对于特定生物学过程以及与口面发育相关的表型结果的调节是必不可少的，以及3）选择的差异表达的靶基因在口面发育期间通过差异甲基化区域进行表观遗传学调节。 公共卫生相关性：口面裂是人类最常见的出生缺陷之一，它会导致婴儿喂养困难，呼吸和语言障碍。本申请中提出的研究旨在促进我们对控制口面区域发育的复杂机制的理解。这项研究计划将采用一种新的生物信息学方法，并将利用模拟人类口面发育的小鼠模型，研究哺乳动物口面发育过程中基因表达的表观遗传调控作用。成功完成拟议的研究将提供一个更好的洞察力的具体控制机制，是重要的口面发育，并将最终揭示潜在的机制分裂。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to elucidate the role of epigenetic regulation of gene expression during mammalian orofacial development. Formation of the mammalian orofacial tissue is a multifaceted, synchronized developmental process involving cell migration, proliferation, differentiation, apoptosis, and synthesis of extracellular matrix. All these critical cellular processes are under the control of a variety of genes encoding growth and differentiation factors, signaling mediators, transcription factors and extracellular matrix proteins, whose expression is controlled, in turn, by epigenetically-modulated regulatory elements. Disruption of any one of these processes can lead to orofacial clefting. Emerging evidence strongly supports the importance of epigenetic mechanisms controlling the expression of key genes critical for orofacial ontogenesis. Recent studies from our lab have demonstrated that precise patterns of differential gene methylation and expression occur in embryonic orofacial tissue. Preliminary data revealed several epigenetically regulated genes which have documented critical roles in orofacial morphogenesis. We thus propose to test the hypothesis that regulation of differentially-expressed genes via differentially methylated regions, is essential for proper development of the embryonic orofacial region. Three hypothesis-driven specific aims will be pursued: 1) Differentially expressed genes encoding mRNAs are epigenetically regulated during orofacial development. 2) Differentially expressed and epigenetically regulated gene transcripts are essential for the regulation of specific biological processes as well as phenotypic outcomes associated with orofacial development, and 3) Selected differentially-expressed target genes are epigenetically regulated via differentially methylated regions during orofacial development. PUBLIC HEALTH RELEVANCE: Orofacial clefts are amongst the most prevalent birth defects in humans, which can lead to difficulties in infant feeding, breathing and speech impairment. Studies proposed in the current application are designed to advance our understanding of the complex mechanisms that control development of the orofacial region. This research proposal will adopt a novel bioinformatic approach and will utilize a mouse model that mimics human orofacial development, to investigate the role of epigenetic regulation of gene expression during mammalian orofacial development. Successful completion of the proposed studies will provide a better insight of the specific control mechanisms that are important in orofacial development and will ultimately reveal potential mechanisms of clefting.