Histone Demethylases and Regulation of Chromatin and Transcription in Eukaryotes

真核生物中组蛋白去甲基化酶以及染色质和转录的调节

基本信息

批准号：
7826952
负责人：
Yang Shi
金额：
$ 14.58万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-13 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7826952
关键词：
Acetylation Address Androgen Receptor Binding Biochemical Biological Process Biology Cell Nucleus Cell Proliferation Cell division Centromere Chromatin Chromatin Structure Chromosome Segregation Complex Coupled Dissection Enzymes Epigenetic Process Euchromatin Eukaryota Event Fission Yeast Gene Expression Regulation Genes Genetic Genetic Transcription Genome HDAC1 gene HDAC2 gene Hela Cells Heterochromatin Histone H3 Histones Homologous Gene Human Investigation Knock-out Life Light Link Lipid Binding Lipids Lysine Malignant Neoplasms Mediating Methylation Methyltransferase Modification Molecular Mutation N-terminal Organism Phosphorylation Plants Play Proteins Proteome Recombinants Regulation Reporting Repression Research Personnel Role SANT Domain Signal Transduction System Tail Technology Transcriptional Regulation Ubiquitination Yang Zinc Fingers base demethylation histone modification homeodomain human HMG20B protein in vitro activity in vivo insight interest novel promoter telomere tumorigenesis

项目摘要

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.

描述（由申请人提供）：组蛋白N末端尾巴的共价修饰（磷酸化，乙酰化，泛素化和甲基化）显着影响染色质结构和基因转录。尽管这些修饰中的许多修饰都是通过相反活性的酶动态调节的，但长期以来，组蛋白甲基化一直被认为是“永久”修饰。我们最近发现了第一个组蛋白脱甲基LSD1（赖氨酸特异性脱甲基酶1），它通过脱甲基化组蛋白H3赖氨酸4（H3-K4）抑制转录，表明类似其他组蛋白修饰的组蛋白甲基化也受到动态调节。我们的发现提出了许多重要而令人兴奋的问题。例如，如何调节LSD1介导的脱甲基化？ LSD1的生物学功能是什么？我们的初步发现表明，LSD1相关因素BHC80在调节由LSD1介导的H3-K4脱甲基化的染色质事件中可能具有非常令人兴奋的作用，以及与脂质信号传导的可能联系。对BHC80调节LSD1的机制的研究是该应用的重点。为了了解组蛋白脱甲基酶的生物学和体内作用机理，我们将分析S. pombe LSD1同源物，SPBC146.09C和SPAC23E2.02中的作用。 POMBE异染色质的特征是H3-K9甲基化和H3-K4低甲基化，这与LSD1同源物在异染色质中的可能作用一致。通过组蛋白修饰对基因表达的表观遗传调节已与包括癌症在内的多种病理状况有关。因此，对异染色质以及斑塑素基因转录中脱甲基酶的理解将不仅为染色质生物学，而且还提供了细胞增殖的控制和肿瘤发生的新见解。根据我们令人兴奋的初始结果，提出的研究可能会导致新的范式，从而显着影响我们对真核染色质和转录调控的看法。