Histone Demethylation A Novel Mechanism in Hormone-Mediated Gene Regulation

组蛋白去甲基化是激素介导的基因调控的新机制

• 批准号: 7467859
• 负责人: Yujiang Geno Shi
• 金额: $ 37.32万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467859
• 关键词: Androgen Receptor; Androgens; Biochemical; Biological; Biological Process; Biology; Brain; Chromatin; Chromatin Structure; Complex; Data; Development; Disease; Elements; Embryonic Development; Epigenetic Process; Estrogen Receptors; Event; Family; Gene Activation; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Genomics; Glucocorticoids; Goals; Hela Cells; Histone Acetylation; Histone Deacetylase; Histone Deacetylation; Histones; Hormone Responsive; Hormones; Human; Human Pathology; Light; Link; Lysine; Maintenance; Mediating; Methylation; Modeling; Modification; Molecular; Molecular Models; Nature; Nuclear Hormone Receptors; Nuclear Receptors; Oncogenic; Pathology; Physiology; Play; Receptor Signaling; Recruitment Activity; Regulation; Reporting; Repression; Research; Role; Signal Transduction; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Vitamin D3 Receptor; cell growth; demethylation; gene repression; histone modification; human NCOR1 protein; insight; molecular modeling; novel; promoter; protein complex; receptor; research study; stem cell differentiation; steroid hormone receptor; tumorigenesis

DESCRIPTION (provided by applicant): Histone modifications provide a mechanism for regulating the diverse structural and functional features of chromatin, including control of gene regulation and maintenance of genomic integrity. Histone modifications play important roles in cell growth and survival, differentiation, embryonic development, and their related pathologies, including oncogenic transformation. Recently, we have made the exciting discovery of the first bona fide histone demethylase LSD1 (Lysine-Specific Demethylase 1). The identification of LSD1 as an H3-lysine 4 (H3-K4) specific histone demethylase revealed the reversible nature of histone methylation. It not only settled the longstanding debate regarding histone demethylation, but also represented a major advance in our understanding of epigenetic gene regulation. LSD1 has also been found in a variety of multi-subunit complexes involved in gene regulation. It is a coregulator for androgen receptor mediated gene regulation, suggesting that histone demethylation may serve as a fundamental mechanism for hormone action at the transcription level. The focus of our research is on the regulation of histone demethylase(s) and the biological consequences of histone demethylation in nuclear receptor mediated gene regulation. These are fundamental events in hormone-dependent biological processes and are important for stem cell differentiation and embryonic development. Using LSD1 as the first molecular model, we aim to define histone demethylation as a novel, yet widespread regulatory mechanism for steroid hormone receptor (e.g. androgen, glucocorticoid, and thyroid receptors) action on target genes. Data derived from these studies will contribute to the rapidly advancing and groundbreaking field of epigenetics. The findings from these studies will provide significant insights into the mechanisms underlying histone demethylation as it relates to nuclear hormone receptor mediated gene regulation. They will also greatly contribute to our understanding of hormone physiology and a variety of human pathologies, including tumorigenesis and developmental anomalies.Histone modifications provide a mechanism for regulating the diverse structural and functional features of chromatin, including control of gene regulation and maintenance of genomic integrity. Histone modifications play important roles in cell growth and survival, differentiation, embryonic development, and their related pathologies, including oncogenic transformation. The focus of our research is on the regulation of histone demethylase(s) and the biological consequences of histone demethylation in nuclear receptor mediated gene regulation. These are fundamental events in hormone-dependent biological processes and are important for stem cell differentiation and embryonic development.

描述（由申请人提供）：组蛋白修饰提供了一种调节染色质不同结构和功能特征的机制，包括控制基因调控和维持基因组完整性。组蛋白修饰在细胞生长和存活、分化、胚胎发育及其相关病理学（包括致癌转化）中起重要作用。最近，我们发现了第一个真正的组蛋白去甲基化酶LSD 1（赖氨酸特异性去甲基化酶1）。LSD 1作为H3-赖氨酸4（H3-K4）特异性组蛋白去甲基化酶的鉴定揭示了组蛋白甲基化的可逆性质。它不仅解决了关于组蛋白去甲基化的长期争论，而且代表了我们对表观遗传基因调控的理解的重大进展。LSD 1也被发现存在于多种参与基因调控的多亚基复合物中。它是雄激素受体介导的基因调控的辅助调节因子，这表明组蛋白去甲基化可能是转录水平上激素作用的基本机制。 我们的研究重点是组蛋白去甲基化酶的调控以及组蛋白去甲基化在核受体介导的基因调控中的生物学后果。这些都是依赖于胚胎干细胞的生物学过程中的基本事件，对干细胞分化和胚胎发育很重要。使用LSD 1作为第一个分子模型，我们的目标是将组蛋白去甲基化定义为类固醇激素受体（例如雄激素，糖皮质激素和甲状腺受体）对靶基因作用的一种新的，但广泛的调节机制。从这些研究中获得的数据将有助于表观遗传学的快速发展和突破性领域。这些研究的发现将为深入了解组蛋白去甲基化的机制提供重要见解，因为它与核激素受体介导的基因调控有关。它们也将极大地有助于我们了解激素生理学和各种人类病理学，包括肿瘤发生和发育异常。组蛋白修饰提供了一种调节染色质不同结构和功能特征的机制，包括控制基因调控和维持基因组完整性。组蛋白修饰在细胞生长和存活、分化、胚胎发育及其相关病理学（包括致癌转化）中起重要作用。 我们的研究重点是组蛋白去甲基化酶的调控以及组蛋白去甲基化在核受体介导的基因调控中的生物学后果。这些都是依赖于胚胎干细胞的生物学过程中的基本事件，对干细胞分化和胚胎发育很重要。