Regulation of transcription and tumor suppression by MTG family members

描述（由申请人提供）：两个髓系易位基因（MTG）家族成员MTG 8和MTG 16在急性髓系白血病中被染色体易位破坏。此外，癌症基因组图谱（TCGA）和其他大型测序研究已经确定了MTG家族成员中分散在整个基因体中的突变，这表明这些突变可能是失活突变。与这种解释一致，MTG 16在霍奇金淋巴瘤中受到DNA甲基化的影响，而MTG 16和MTGR 1在结肠癌中表达不足。我们的初步数据支持这一假设，即失活突变加速了三种不同小鼠癌症模型的肿瘤发生。从机制上讲，MTG家族成员通过与CDK 9和Tif 1（或“月光”）的关联，在RNA Pol II暂停和延长的水平上与转录控制密切相关。我们的初步数据显示，MTG家族成员与转录延伸机制的关键调控因子直接接触，以负调控基因表达。重要的是，MTG家族成员的癌症相关突变会影响这些与延伸因子的接触。因此，我们假设，MTG依赖的转录暂停/延长的调节是肿瘤抑制的关键事件，这种负调控的释放允许转录暂停控制的基因的激活。通过使用遗传学和创新的新方法（如转录测序的全局运行）定义MTG调节转录延伸的机制，并通过使用肿瘤发生的小鼠模型，我们将直接测试这一假设，并定义在暂停和延伸水平上转录控制的丧失如何有助于肿瘤的发展。

DESCRIPTION (provided by applicant): Two myeloid translocation gene (MTG) family members, MTG8 and MTG16 are disrupted by chromosomal translocations in acute myeloid leukemia. In addition, the caner genome atlas (TCGA) and other large sequencing studies have identified mutations in MTG family members that are scattered throughout the gene body, suggesting that these may be inactivating mutations. Consistent with this interpretation, MTG16 is affected by DNA methylation in Hodgkin's lymphoma and MTG16 and MTGR1 are under expressed in colon cancer. Our preliminary data support this hypothesis in that inactivating mutations accelerated tumorigenesis in three separate mouse models of cancer. Mechanistically, MTG family members have been tangentially linked to transcriptional control at the level of RNA Pol II pausing and elongation through associations with CDK9 and Tif1 (or "Moonshine"). Our preliminary data shows that MTG family members make direct contacts with key regulators of the transcriptional elongation machinery to negatively regulate gene expression. Importantly, cancer associated mutations of MTG family members affect these contacts with elongation factors. Thus, we hypothesize that MTG-dependent regulation of transcriptional pausing/elongation is a key event in tumor suppression and that release of this negative regulation allows activation of genes controlled by transcriptional pausing. By defining the mechanism by which MTGs regulate transcriptional elongation using genetics and innovative new approaches such as global run on transcription sequencing, and by using mouse models of tumorigenesis, we will directly test this hypothesis and define how loss of transcriptional control at the level of pausing and elongation contributes to tumor development.