Role of novel onco-histone mutations in B-cell malignancies

编码在DNA中的遗传信息由 染色质的背景。由于基因组序列在整个发育过程中基本保持不变， 染色质修饰是基因组和调控输入之间的关键界面。组蛋白 蛋白质是染色质的主要成分；四种核心组蛋白类型组成核小体颗粒， 染色质基本单位。第五种类型，连接物组蛋白H1，结合核小体和连接物DNA之间。 尽管近年来在了解核心组蛋白功能方面取得了重大进展，但许多 链接器组蛋白H1的生物学特性尚不清楚。链接器组蛋白H1的突变最近在 大约30%的滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤，我们已经确定了H1 结节性硬化症亚型中85%的霍奇金淋巴瘤的突变。根据初步数据，我们 假设H1 茎 受限 依存性 克隆人。 B类 正在发生 引起 合作 高高在上 免疫 这 控制 至 肿瘤 异位诱导胚胎功能缺失诱导淋巴肿大 在GC B细胞中给予无限自我更新的细胞(ESC)基因表达特征 它们的繁殖能力。我们认为，ESC基因的表达使B细胞从 T细胞有助于生存和分裂，导致异常的癌前B细胞的扩张 从机制上讲，我们认为H1参与了PRC2的募集和染色质的压缩 细胞分化，从而抑制ESC基因。因此，通过体细胞突变而丧失H1的功能 生发中心B细胞导致PRC2和H3K27甲基化减少和重新分布 染色质解压与ESC基因的表达。最后，我们预测H1功能丧失 与bcl2等淋巴瘤癌基因共同诱导恶性转化。这个 这项拟议研究的目的是揭示连接子组蛋白对体液的贡献 生物化学和生物学角度的反应和淋巴肿大。我们将实现 通过以下具体目标：1)确定要求H1通过的作用和机制 GC反应；2)确定H1突变重新编程表观基因组的机制 驱动淋巴增生症；以及3)确定H1体型是否以及如何作为真正的淋巴瘤发挥作用 抑制者。对H1的研究是相当具有挑战性的，但我们正准备独一无二地揭开 气相色谱 典则 L 我 分子 通过将领导者聚集在一起，在淋巴癌发生中H1突变的细节和功能后果 在转录调控、染色质、表观遗传调控和淋巴肿大等领域。

The genetic information encoded in DNA is packaged and interpreted by the cellular machinery within the context of chromatin. As the genome sequence remains largely unchanged throughout development, chromatin modifications represent a critical interface between the genome and regulatory inputs. Histone proteins are major constituents of chromatin; four core histone types make up the nucleosome particle, the basic unit of chromatin. The fifth type, linker histone H1, binds the nucleosome and the linker DNA between. Whereas the progress in understanding the function of core histones is significant in recent years, much of the linker histone H1 biology remains unknown. Mutations in linker histone H1 have been recently reported in approximately 30% of follicular lymphomas and diffuse large B cell lymphomas, and we have identified H1 mutations in 85% of Hodgkin's lymphomas of the nodular sclerosis subtype. Based on preliminary data, we hypothesize that H1 stem restricted dependency clones. B occurring causing cooperates overarching immune this control to tumor isoform loss of function induces lymphomagenesis by ectopically inducing an embryonic cell (ESC) gene expression signature that imparts unlimited self-renewal in GC B-cells that are otherwise in their ability to proliferate. We propose that ESC gene expression frees B-cells from their on T-cell help to survive and divide, resulting in expansion of aberrant pre-neoplastic B-cells Mechanistically, we propose that H1 is involved in PRC2 recruitment and chromatin compaction during cell differentiation, thereby repressing ESC genes. Thus, loss of function of H1 through somatic mutations in germinal center B cells results in reduction and redistribution PRC2 and H3K27 methylation chromatin decompaction and expression of ESC genes. Finally, we predict that H1 loss of function with lymphoma oncogenes such as BCL2 to induce malignant transformation. The goa of the proposed research is to reveal the contributions of linker histones to the humoral response and lymphomagenesis from both biochemical and biological perspectives. We will achieve through the following specific aims: 1) Determine the role and mechanism through which H1 is required to the GC reaction; 2) Determine the mechanism through which H1 mutations reprogram the epigenome drive lymphomagenesis; and 3) Determine whether and how H1 soforms function as bona fide lymphoma suppressors. The study of H1 is quite challenging, but we are uniquely poised to unravel GC canonical l i the molecular details and functional consequences of H1mutations in lymphoid carcinogenesis by bringing together leaders in the field of transcriptional regulation, chromatin, epigenetic regulation and lymphomagenesis.