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表观遗传调控基因表达在哺乳动物口腔面部发育中的作用。哺乳动物口腔组织的形成是一个多方面、同步的发育过程，涉及细胞的迁移、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在一种 多种编码生长和分化因子、信号调节因子、转录因子和细胞外基质蛋白的基因，其表达又受表观遗传调节元件的调控。这些过程中的任何一个过程的中断都可能导致口腔裂隙。新出现的证据有力地支持了表观遗传机制的重要性，这些机制控制着对口腔面部个体发育至关重要的关键基因的表达。我们实验室最近的研究表明，在胚胎口腔面部组织中存在差异基因甲基化和表达的精确模式。初步数据揭示了几个表观遗传调控基因，它们证明了在口腔面部形态发生中的关键作用。因此，我们建议检验这一假设，即通过差异甲基化区域调节差异表达的基因，对于胚胎口面部区域的正常发育至关重要。将追求三个假说驱动的特定目标：1)编码mRNAs的差异表达基因在口腔面部发育过程中受表观遗传调控。2)差异表达和表观遗传调控的基因转录本对于特定的生物学过程以及与口腔面部发育相关的表型结果的调控是必不可少的；3)选定的差异表达的靶基因在口腔面部发育过程中通过差异甲基化区域进行表观遗传调控。 与公共卫生相关：口腔裂是人类最常见的出生缺陷之一，可导致婴儿喂养困难、呼吸困难和语言障碍。目前应用中提出的研究旨在促进我们对控制口面部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腔面部发育的小鼠模型，来研究基因表达的表观遗传调控在哺乳动物口腔面部发育中的作用。成功完成拟议的研究将提供更好的洞察力，了解在口腔面部发育中重要的具体控制机制，并最终揭示潜在的唇裂机制。

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.