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

摘要 真核生物的基因组被包装成染色质，这些染色质由称为核小体的重复单位组成。 核小体由核心组蛋白(H_2A、H_2B、H_3和H_4)的八聚体组成，周围有DNA 包好。组蛋白的第五种类型是H1连接器组蛋白，它以动态的方式与染色质结合， 促进染色质紧凑成更高级的结构。哺乳动物表达11种H1组蛋白亚型 它们在初级序列和调控上有所不同。核心组蛋白的翻译后修饰(PTM) 蛋白质越来越被认为是染色质结构和功能的关键调节因子，影响着许多 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PTMS在表观遗传调控中的作用，其形成的失调导致多种 疾病状态，最明显的是癌症。尽管H1组蛋白主要被视为染色质 结构蛋白，我们实验室的研究揭示了连接子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‘S影响核心组蛋白甲基化的机制及核心组蛋白PTMS的全方位调控 到了H1，子类型是未知的。H1组蛋白基因在几种癌症中经常发生突变，尤其是 淋巴瘤。然而，这些突变对H1‘S表观遗传调控功能的影响尚未得到研究 学习。我们建议确定某些H1亚型抑制H3K4甲基化的机制，以及 激活组蛋白标记的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 癌相关H1蛋白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连接器组蛋白在表观遗传调控中的新机制 无论是正常细胞还是癌细胞。

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.