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Epigenetic activity of normal and cancer-associated mutant H1 linker histones

正常和癌症相关突变 H1 连接组蛋白的表观遗传活性

基本信息

批准号：
9316320
负责人：
Sean Healton
金额：
$ 4.4万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-18 至 2020-07-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316320
关键词：
Address Affect B-Cell Lymphomas Binding Biological Assay Cancer Biology Cell Line Chromatin Chromatin Structure Chronic Lymphocytic Leukemia DNA DNA Methylation DNA Modification Methylases DNA Repair Deposition Disease Drosophila genus Environment Enzymes Epigenetic Process Eukaryotic Cell Follicular Lymphoma Genes Genetic Transcription Genome Goals Higher Order Chromatin Structure Histone H1 Histone H1(s)Histone H2A Histone H4 Histones Human In Vitro Laboratories Lead Link Lymphoma Lysine Malignant Neoplasms Mammals Mediating Methylation Methyltransferase Molecular Mus Mutate Mutation N-terminal Normal Cell Nucleosomes Pathogenesis Patients Physical condensation Play Post-Translational Protein Processing Process Property Proteins Reader Recombinants Recruitment Activity Recurrence Regulation Reporting Role SPT6 Protein Site Specificity Tail Testing Work base cancer cell enzyme activity epigenetic regulation histone methylation histone methyltransferase in vivo lymphoid neoplasm mutant novel novel therapeutics reconstitution tumor

项目摘要

Abstract The eukaryotic genome is packaged into chromatin formed of repeating units called nucleosomes. Nucleosomes consist of an octamer of core histone proteins (H2A, H2B, H3 and H4) around which DNA is wrapped. A fifth type of histone, the H1 linker histone, associates with chromatin in a dynamic fashion, promoting compaction of chromatin into higher order structures. Mammals express 11 H1 histone subtypes that differ in primary sequence and regulation. Post-translational modifications (PTMs) to the core histone proteins are increasingly recognized as key regulators of chromatin structure and function, affecting many processes occurring on DNA, including transcription, replication and DNA repair. Given the central role of core histone PTMs in epigenetic regulation, it is not surprising that dysregulation of their formation leads to a variety of disease states, most notably cancer. Although the H1 histone has been viewed primarily as a chromatin structural protein, studies from our lab have revealed novel roles for linker histones in epigenetic regulation, including subtype-specific regulation of core histone methylation and DNA methylation. However, the molecular mechanisms by which H1's affect core histone methylation and the full range of core histone PTMs regulated by H1 subtypes are unknown. H1 histone genes are frequently mutated in a several cancers, particularly lymphomas. However, the effects of these mutations on H1's functions in epigenetic regulation have not been studied. We propose to determine the mechanism by which certain H1 subtypes inhibit H3K4 methylation, an activating histone mark whose aberrant deposition is linked to several cancers. We also propose to explore H1-mediated regulation of methylation at other residues in H3 and H4 histones. Finally, we seek to investigate the consequences of cancer-associated mutations in H1 proteins on their functions in epigenetic regulation. Successful completion of this work will reveal novel mechanisms of epigenetic regulation by linker histones in both normal and cancer cells.

摘要真核生物的基因组被包装到由称为核小体的重复单位形成的染色质中。核小体由核心组蛋白的八聚体（H2A、H2B、H3和H4）组成，DNA围绕所述八聚体。包装好了第五种类型的组蛋白，H1接头组蛋白，以动态方式与染色质结合，促进染色质压缩成高级结构。哺乳动物表达11种H1组蛋白亚型它们在一级序列和调控上不同。核心组蛋白的翻译后修饰（PTM）蛋白质越来越多地被认为是染色质结构和功能的关键调节剂，影响许多发生在DNA上的过程，包括转录，复制和DNA修复。鉴于核心的核心作用，组蛋白PTM在表观遗传调控中，其形成的失调导致各种疾病状态，尤其是癌症。虽然H1组蛋白主要被看作是染色质，结构蛋白，我们实验室的研究揭示了连接组蛋白在表观遗传调控中的新作用，包括核心组蛋白甲基化和DNA甲基化的亚型特异性调节。然而，分子 H1影响核心组蛋白甲基化的机制以及核心组蛋白PTMs的全部调节 H1亚型是未知的。H1组蛋白基因在几种癌症中经常发生突变，特别是淋巴瘤然而，这些突变对H1在表观遗传调控中的功能的影响还没有被证实。研究了我们建议确定某些H1亚型抑制H3K4甲基化的机制，激活组蛋白标记，其异常沉积与几种癌症有关。我们还建议探索 H1介导的H3和H4组蛋白中其他残基甲基化的调节。最后，我们试图调查 H1蛋白的癌症相关突变对其表观遗传调控功能的影响。这项工作的成功完成将揭示新的机制，表观遗传调控的连接组蛋白，正常细胞和癌细胞。