Regulation of transcription and tumor suppression by MTG family members

MTG 家族成员对转录和肿瘤抑制的调节

基本信息

批准号：
8696545
负责人：
SCOTT W HIEBERT
金额：
$ 36.36万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-13 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696545
关键词：
Acute Myelocytic Leukemia Address Affect Atlases Binding C-terminal CBFA2T1 gene Chimeric Proteins Chromatin Chromosomal translocation Chromosomes, Human, Pair 16 Chromosomes, Human, Pair 8 Colon Carcinoma Complex DNA Binding DNA Binding Domain DNA Methylation DNA Polymerase II Data Development E protein Elongation Factor Enzymes Event Family member Gene Activation Gene Expression Gene Family Gene Proteins Genes Genetic Genetic Transcription Genome Histones Hodgkin Disease Length Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Modeling Mus Mutate Mutation Myelogenous N-terminal NCOR1 gene NCOR2 gene Phenotype Physiological Point Mutation Proteomics RNA RNA Splicing RUNX1 gene Recruitment Activity Regulation Role Running Solid Neoplasm TAL1 gene TCF3 gene TCF7L2 gene Testing The Cancer Genome Atlas Transcription Elongation Transcriptional Elongation Factors Transcriptional Regulation Tumor Suppression Variant Work Yeasts gene repression histone methyltransferase in vivo innovation leukemia malignant breast neoplasm mouse model mutant novel novel strategies public health relevance release factor research study t(8 21)(q22 q22)transcription factor transcriptional intermediary factor 1 tumor tumorigenesis yeast two hybrid system

项目摘要

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.

描述（由申请人提供）：两个髓样转运基因（MTG）家庭成员MTG8和MTG16受到急性髓样白血病的染色体易位的破坏。此外，Caner基因组图集（TCGA）和其他大型测序研究已经鉴定出散布在整个基因体内的MTG家族成员中的突变，这表明这些突变可能正在灭活突变。与这种解释一致，MTG16受Hodgkin淋巴瘤中DNA甲基化的影响，MTG16和MTGR1在结肠癌中表达。我们的初步数据支持了这一假设，因为在三种单独的癌症小鼠模型中，灭活突变加速了肿瘤发生。从机械上讲，通过与CDK9和TIF1（或“ Moonshine”）的关联，MTG家族成员与RNA POL II暂停和伸长水平上的转录控制与转录控制。我们的初步数据表明，MTG家族成员与转录伸长机械的关键调节器直接接触，以负调节基因表达。重要的是，癌症与MTG家族成员相关的突变会影响这些接触与伸长因子的接触。因此，我们假设转录暂停/伸长的MTG依赖性调节是肿瘤抑制的关键事件，并且该阴性调节的释放允许激活由转录暂停控制的基因。通过定义MTGS使用遗传学和创新的新方法（例如在转录测序上运行的全局运行）以及使用肿瘤发生的小鼠模型来调节转录伸长的机制，我们将直接检验该假设并定义如何在抑制水平和延长水平上转录控制的损失有助于肿瘤发育。