Histone Demethylases and Regulation of Chromatin and Transcription in Eukaryotes

描述（由申请人提供）：组蛋白N-末端尾部的共价修饰（磷酸化、乙酰化、泛素化和甲基化）显著影响染色质结构和基因转录。虽然这些修饰中的许多是由相反活性的酶动态调节的，但组蛋白甲基化长期以来被认为是“永久性”修饰。我们最近发现了第一个组蛋白去甲基化酶LSD 1（赖氨酸特异性去甲基化酶1），它通过使组蛋白H3赖氨酸4（H3-K4）去甲基化来抑制转录，这表明组蛋白甲基化与其他组蛋白修饰一样，也是动态调节的。我们的发现提出了一些重要而令人兴奋的问题。例如，LSD 1介导的去甲基化是如何调节的？LSD 1的生物学功能是什么？我们的初步研究结果表明，BHC 80，LSD 1相关因子，在调节LSD 1介导的H3-K4去甲基化后的染色质事件中可能具有非常令人兴奋的作用，并且可能与脂质信号传导有关。研究BHC 80调节LSD 1的机制是本申请的重点。为了了解组蛋白去甲基化酶的生物学和体内作用机制，我们将分析S。粟酒裂殖酵母LSD 1同源物SPBC146.09C和SPAC23E2.02，在常染色质和异染色质生物学中。粟属异染色质的特征是H3-K9甲基化和H3-K4低甲基化，这与LSD 1同源物在异染色质中可能发挥的作用一致。通过组蛋白修饰的基因表达的表观遗传调控与包括癌症在内的多种病理状况有关。因此，异染色质以及常染色质基因转录的去甲基化酶的理解将提供新的见解，不仅染色质生物学，而且细胞增殖控制和肿瘤发生一般。基于我们令人兴奋的初步结果，所提出的研究可能会导致新的范式，这将显着影响我们的真核染色质和转录调控的观点。

DESCRIPTION (provided by applicant): Covalent modifications (phosphorylation, acetylation, ubiquitination and methylation) of histone N-terminal tails significantly impact chromatin structure and gene transcription. While many of these modifications are regulated dynamically by enzymes of opposing activities, histone methylation has long been considered a "permanent" modification. We have recently discovered the first histone demethylase LSD1 (Lysine Specific Demethylase 1), which represses transcription by demethylating histone H3 lysine 4 (H3-K4), demonstrating that histone methylation, like other histone modifications, is also regulated dynamically. Our findings raise a number of important and exciting questions. For instance, how is LSD1-mediated demethylation regulated? What are the biological functions of LSD1? Our preliminary findings suggest a potentially very exciting role for BHC80, an LSD1 associated factor, in regulating chromatin events post H3-K4 demethylation mediated by LSD1, and a possible connection to lipid signaling. Investigation of mechanisms by which BHC80 regulates LSD1 is a focus of this application. To understand the biology and in vivo mechanism of action of histone demethylases, we will analyze the roles of S. pombe LSD1 homologs, SPBC146.09C and SPAC23E2.02, in both euchromatin and heterochromatin biology. Pombe heterochromatin is characterized by H3-K9 methylation and H3-K4 hypomethylation, which is consistent with a possible role for LSD1 homologs in heterochromatin. Epigenetic regulation of gene expression via histone modifications has been linked to multiple pathological conditions including cancer. Thus, an understanding of demethylases in heterochromatin as well as euchromatin gene transcription will provide new insights not only into chromatin biology but also cell proliferation control and tumorigenesis in general. Based on our exciting initial results, the proposed studies are likely to result in new paradigms that will significantly impact our views of eukaryotic chromatin and transcriptional regulation.