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.
Myeloid Translocation Gene (MTG) family members are disrupted by chromosomal translocations in acute myeloid leukemia, are silenced in Hodgkin's lymphoma and are mutated in over 10 different solid tumor types. This work will examine the role of MTG proteins in the control of gene expression at the level of transcriptional pausing and elongation. In addition, this proposal will determine the physiological function of cancer-associated mutations in transcriptional control and tumor development in vivo.