Histone Demethylases and Their Regulation

描述(申请人提供)：阐明与基因表达的表观遗传调控有关的分子机制仍然是许多生物学研究领域的“圣杯”。最近，我们有了第一个真正的组蛋白去甲基酶的令人兴奋的发现。赖氨酸特异的脱甲基酶1(LSD1)是一种H3-赖氨酸4(H3-K4)特异的组蛋白去甲基酶，它的发现证实了长期以来关于组蛋白甲基化可逆性的推测，并代表着我们对表观遗传调控的理解的重大进展。LSD1是一种依赖于FAD的转录辅助抑制因子，广泛存在于多种多亚单位复合体中。对这些染色质调节复合体及其组分的活性和调控的精确机制的详细了解是最终理解基因组组织和基因组信息处理的本质的关键一步。我们的研究重点是组蛋白去甲基酶的调控以及组蛋白去甲基化在基因调控和DNA修复中的生物学后果，这两个事件是干细胞分化、胚胎发育和癌症进展过程中最基本的两个事件。此外，我们打算鉴定其他新的组蛋白去甲基酶，包括那些可能表现出替代底物特异性和可能不同的化学机制的酶。这些数据将进一步促进这一快速发展和突破性的表观遗传学领域。本文描述的研究结果将对组蛋白去甲基化的机制提供具体的见解，并将扩大我们对一般表观遗传调控的知识，因为它几乎涉及基因组相关生物学的方方面面和迅速出现的癌症表观遗传学。这项工作无疑将对包括肿瘤发生和发育异常在内的各种人类病理学产生重大影响。

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.