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，MTG8和MTG16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。与这一解释一致，MTG16在霍奇金淋巴瘤中受DNA甲基化影响，而MTG16和MTGR1在结肠癌中表达不足。我们的初步数据支持这一假设，即灭活突变在三种不同的癌症小鼠模型中加速了肿瘤的发生。从机制上讲，MTG家族成员通过与CDK9和Tif1（或“月光”）的关联，与RNA Pol II暂停和延伸水平的转录控制有切向联系。我们的初步数据表明，MTG家族成员与转录延伸机制的关键调控因子直接接触，从而负向调控基因表达。重要的是，MTG家族成员的癌症相关突变影响这些与伸长因子的接触。因此，我们假设mtg依赖性的转录暂停/延长调控是肿瘤抑制的关键事件，并且这种负调控的释放允许激活由转录暂停控制的基因。通过使用遗传学和创新的方法（如转录测序的全局运行）来定义MTGs调节转录延伸的机制，并通过使用小鼠肿瘤发生模型，我们将直接验证这一假设，并定义在暂停和延伸水平上的转录控制丧失如何促进肿瘤发展。

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.