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: 8537402
• 负责人: Guy Brock
• 金额: $ 25.2万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537402
• 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.

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。