NSD1 Inactivation in Head and Neck Cancer

项目总结 越来越多的证据支持染色质失调在各种人类疾病的发病机制中的作用。 包括癌症在内的疾病，尽管其潜在机制尚不清楚。新近的肿瘤基因组 测序工作已经确定了组蛋白H3赖氨酸36(H3K36)特异性的NSD1的失活突变 甲基转移酶在10-15%的头颈部鳞状细胞癌(HNSCC)中表达，HNSCC是第六大癌症 全世界。本研究的重点是阐明NSD1失活促进的分子机制 HNSCC的发展，并将检验NSD1的生化和遗传失活的中心假设 改变DNA甲基组和转录组以破坏鳞状组织分化并促进HNSCC 体内启动。在指导培训期间，我将对生化基础和功能进行表征 H3赖氨酸36抑制NSD1对蛋氨酸(H3K36M)突变的重要性 与儿科恶性肿瘤有关，并通过我的初步研究在HNSCC中确认。我也会 简介NSD1和H3K36M突变对H3K36甲基化和H3K36基因全基因组分布的影响 DNA甲基化以及转录组。在颁奖期的独立阶段，我建议 探讨NSD1在鳞状组织分化和体内抑制HNSCC中的作用。 综上所述，拟议的研究将为遗传疾病的子集的发病机制提供新的见解。 明确的和表观上不同的HNSCC，可以转化为改善对患者的护理。他们还将 作为我获得化学生物学、计算表观基因组学和小鼠培训的平台 癌症模型将对我作为一名独立调查员的职业发展做出关键贡献 癌症表观遗传学领域。

PROJECT SUMMARY Increasing evidence has supported a role for chromatin misregulation in the pathogenesis of various human diseases including cancer, although the underlying mechanism remains unclear. Recent tumor genome sequencing efforts have identified inactivating mutations in NSD1, a histone H3 lysine 36 (H3K36)-specific methyltransferase, in 10-15% of head and neck squamous cell carcinomas (HNSCC), the sixth leading cancer worldwide. This study focuses on elucidating the molecular mechanisms by which NSD1 inactivation facilitate HNSCC development and will test the central hypothesis that biochemical and genetic inactivation of NSD1 alters DNA methylome and transcriptome to disrupt squamous tissue differentiation and promote HNSCC initiation in vivo. During the mentored training period, I will characterize the biochemical basis and functional importance of NSD1 inhibition by H3 lysine 36 to methionine (H3K36M) mutation, an oncohistone previously associated with pediatric malignancies and identified in HNSCC through my preliminary studies. I will also profile the impact of NSD1 and H3K36M mutations on the genome-wide distribution of H3K36 methylation and DNA methylation as well as on the transcriptome. During the independent phase of the award period, I propose to investigate the function of NSD1 in squamous tissue differentiation and in vivo suppression of HNSCC. Together the proposed studies will provide novel insights into the pathogenesis of a subset of genetically defined and epigenetically distinct HNSCC that can translate into improved care for patients. They will also serve as a platform for me to obtain trainings in chemical biology, computational epigenomics and mouse models of cancer that will critically contribute to my career development as an independent investigator in the field of cancer epigenetics.