Histone Demethylases and Their Regulation

组蛋白去甲基化酶及其调控

• 批准号: 7132876
• 负责人: Yujiang Geno Shi
• 金额: $ 33.51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7132876
• 关键词: DNA repair; HeLa cells; chromatin immunoprecipitation; chymotrypsin; cofactor; conformation; electrospray ionization mass spectrometry; enzyme activity; enzyme mechanism; epigenetics; gas chromatography mass spectrometry; genetic regulation; histones; methylation; oxidoreductase; point mutation; posttranslational modifications; protein localization; protein purification; proteolysis

DESCRIPTION (provided by applicant): Elucidation of the molecular mechanisms involved in the epigenetic regulation of gene expression remains the 'holy grail' for many research fields in biology. Recently, we made the exciting discovery of the first bona fide histone demethylase. The identification of Lysine-Specific Demethylase 1(LSD1), an H3-lysine 4 (H3- K4) specific histone demethylase confirmed the long held speculation regarding the reversible nature of histone methylation, and represents a major advance in our understanding of epigenetic regulation. LSD1 functions as an FAD dependent transcriptional corepressor and is found in a variety of multi-subunit complexes. A detailed knowledge of the precise mechanisms underlying the activity and regulation of these chromatin modulating complexes and their components is an essential step toward the eventual understanding of the essence of both genome organization and genomic information processing. The focus of our research is on the regulation of histone demethylases and the biological consequences of histone demethylation in gene regulation and DNA repair, which are two of the most essential events during stem cell differentiation, embryonic development, and cancer progression. Furthermore, we intend to identify additional novel histone demethylases, including those that may either exhibit alternative substrate specificities and perhaps different chemical mechanisms. These data will contribute further to this quickly moving and groundbreaking field of epigenetics. The findings from the studies described here will provide specific insights into the mechanisms underlying histone demethylation and will expand our knowledge of general epigenetic regulation as it relates to nearly every facet of genome-related biology and rapidly emerging cancer epigenetics. This work will undoubtedly have significant impact on a variety of human pathologies, including tumorigenesis and developmental anomalies.

描述（由申请人提供）：阐明基因表达表观遗传调控所涉及的分子机制仍然是生物学许多研究领域的“圣杯”。最近，我们令人兴奋地发现了第一个真正的组蛋白去甲基酶。赖氨酸特异性去甲基化酶 1 (LSD1) 是一种 H3-赖氨酸 4 (H3-K4) 特异性组蛋白去甲基化酶，其鉴定证实了长期以来关于组蛋白甲基化可逆性质的推测，并代表了我们对表观遗传调控理解的重大进展。 LSD1 作为 FAD 依赖性转录辅阻遏物发挥作用，存在于多种多亚基复合物中。详细了解这些染色质调节复合物及其成分的活性和调节背后的精确机制是最终理解基因组组织和基因组信息处理本质的重要一步。我们研究的重点是组蛋白去甲基化酶的调节以及组蛋白去甲基化在基因调节和 DNA 修复中的生物学后果，这是干细胞分化、胚胎发育和癌症进展过程中最重要的两个事件。此外，我们打算鉴定其他新型组蛋白去甲基酶，包括那些可能表现出替代底物特异性和可能不同化学机制的酶。这些数据将为表观遗传学这一快速发展且具有开创性的领域做出进一步贡献。这里描述的研究结果将为组蛋白去甲基化的机制提供具体的见解，并将扩展我们对一般表观遗传调控的认识，因为它涉及基因组相关生物学和迅速出现的癌症表观遗传学的几乎每个方面。这项工作无疑将对多种人类病理学产生重大影响，包括肿瘤发生和发育异常。