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：
9265416
负责人：
SCOTT W HIEBERT
金额：
$ 36.4万
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/9265416
关键词：
Acute Myelocytic Leukemia Address Affect Atlases Binding C-terminal CBFA2T1 gene Cancer Model Canes Chimeric Proteins Chromatin Chromosomal translocation Chromosomes, Human, Pair 16 Chromosomes, Human, Pair 8 Colon Carcinoma Complex DNA Binding Domain DNA Methylation DNA Polymerase II Data Development E protein Elongation Factor Enzymes Event Family member Gene Activation Gene Expression Gene Proteins Genes Genetic Genetic Transcription Genome Histone Deacetylase Hodgkin Disease Impairment Length Link MLL gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Modeling Mus Mutate Mutation Myelogenous N-terminal NCOR1 gene Phenotype Physiological Point Mutation Proteomics RNA RNA Splicing RUNX1 gene Recruitment Activity Regulation Role Solid Neoplasm TAL1 gene TCF3 gene Testing The Cancer Genome Atlas Transcription Elongation Transcriptional Elongation Factors Transcriptional Regulation Tumor Suppression Variant Work Yeasts experimental study gene repression gene translocation global run on sequencing histone methyltransferase in vivo innovation leukemia leukemogenesis malignant breast neoplasm mouse model mutant novel novel strategies protein E public health relevance release factor t(8 21)(q22 q22)transcription factor 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）：两个髓系易位基因（MTG）家族成员MTG8和MTG16在急性髓系白血病中因染色体易位而被破坏。此外，癌症基因组图谱（TCGA）和其他大型测序研究已经发现MTG家族成员的突变分散在整个基因体中，表明这些可能是失活突变。与这一解释一致，MTG16 在霍奇金淋巴瘤中受到 DNA 甲基化的影响，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，因为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 CDK9 和 Tif1（或“Moonshine”）的关联，与 RNA Pol II 暂停和延伸水平的转录控制相关。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节因子直接接触，从而负向调节基因表达。重要的是，MTG 家族成员的癌症相关突变会影响这些与伸长因子的接触。因此，我们假设转录暂停/延伸的 MTG 依赖性调节是肿瘤抑制的关键事件，并且这种负调节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新方法（例如全局转录测序）来定义 MTG 调节转录延伸的机制，并使用肿瘤发生的小鼠模型，我们将直接检验这一假设并定义在暂停水平上转录控制的丧失是如何发生的。伸长有助于肿瘤的发展。