Histone Demethylases and Their Regulation

这项提案调查了组蛋白赖氨酸去甲基酶LSD2是如何被靶向并保留到 通过其辅因子NPAC主动转录基因体。我们假设NPAC有两面性 通过NPAC的连接区和H3K36me3组蛋白修饰与LSD2相互作用- 通过NPAC的PWWP结构域包含核小体，从而物理地将LSD2连接到 H3K36me3富含功能位点。我们将使用各种NPAC突变和缺失 构建并使用分子生物学和生化方法来确定 NPAC介导LSD2靶向其功能位点的分子机制。 拟议中的研究结果将通过以下方式为分子机制提供重要的见解 哪种NPAC参与了LSD2介导的活跃转录基因的基因调控 身体。如果成功，这项建议有望为我们提供新的见解，让我们了解 辅因子在组蛋白去甲基化调节中的作用和机制 对表观遗传基因调控和染色质生物学的进步产生重大影响。 最终，拟议研究的结果也将为 以表观遗传学为基础的疗法的发展。

This proposal investigates how histone lysine demethylase LSD2 is targeted and retained to actively transcribed gene bodies by its cofactor NPAC. We hypothesize that NPAC has dual interactions with LSD2 via NPAC's linker region and the H3K36me3 histone modification- containing nucleosomes via NPAC's PWWP domain, thereby physically linking LSD2 to H3K36me3-enriched functional sites. We will employ various NPAC mutation and deletion constructs and use molecular biological and biochemical approaches to determine the molecular mechanism underlying NPAC-mediated targeting of LSD2 to its functional sites. Results from the proposed study will offer significant insight into the molecular mechanism by which NPAC contributes to LSD2 mediated gene regulation within actively transcribed gene bodies. If successful, the proposal is expected to offer new insight into our understanding of the role and mechanism of action of cofactors in regulation of histone demethylation, and make significant impact on the advancement of epigenetic gene regulation and chromatin biology. Ultimately, findings from the proposed study will also provide important information for the development of epigenetic-based therapeutics.