Integrated Analysis: Epigenetic Regulation of Gene Expression During Orofacial De

综合分析：口面部脱发过程中基因表达的表观遗传调控

• 批准号: 8385921
• 负责人: Guy Brock
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385921
• 关键词: Adopted; Apoptosis; Back; Bioinformatics; Biological; Biological Process; Breathing; Candidate Disease Gene; Cell physiology; Cleaved cell; Complex; Congenital Abnormality; CpG dinucleotide; Data; Development; Developmental Process; Differentiation and Growth; Embryo; Embryonic Development; Epigenetic Process; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Global Change; Goals; Human; Impairment; Infant; Investigation; Lead; Mediator of activation protein; Messenger RNA; Methods; Methylation; Modification; Molecular; Morphogenesis; Outcome; Pathway interactions; Pattern; Process; Regulation; Regulatory Element; Research Proposals; Role; Signal Pathway; Signal Transduction; Speech; Testing; Time; Tissues; Transcript; base; bisulfite; cell motility; design; feeding; insight; mRNA Expression; mouse model; novel; novel strategies; orofacial; transcription factor

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.

描述（由申请人提供）：该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节的作用。哺乳动物类似组织的形成是一种多方面的，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在A的控制之下 编码生长和分化因子，信号介质，转录因子和细胞外基质蛋白的各种基因，这些基因的表达又通过表观遗传调节的调节元件来控制。这些过程中的任何一个都可能导致口面裂。新兴的证据强烈支持控制对口面异化至关重要的关键基因表达的表观遗传机制的重要性。我们实验室的最新研究表明，胚胎类种族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节的基因，这些基因已记录了口面形态发生中的关键作用。因此，我们建议检验以下假设：通过差异甲基化区域调节差异表达的基因对于适当发展胚胎口面区域至关重要。将追求三个假设驱动的特定目的：1）编码mRNA的差异表达基因在口面发育过程中受到表观遗传调节。 2）差异表达和表观遗传调节的基因转录物对于调节特定生物学过程以及与口面发育相关的表型结局至关重要，3）在口面相期间，通过差异性甲基化区域对选定的差异表达的靶基因进行表观遗传学调节。 公共卫生相关性：口腔裂缝是人类最普遍的先天缺陷之一，这可能导致婴儿喂养，呼吸和言语障碍的困难。当前应用中提出的研究旨在促进我们对控制口面区域发展的复杂机制的理解。该研究建议将采用一种新颖的生物信息学方法，并将利用模仿人体形成发育的小鼠模型来研究基因表达在哺乳动物类种族发育过程中基因表达的作用。成功完成拟议的研究将更好地了解在口面发展中很重要的特定控制机制，并最终揭示了裂曲的潜在机制。