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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA178030-03
Application #
9055662
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2014-05-13
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
Heaster, Tiffany M; Walsh, Alex J; Zhao, Yue et al. (2018) Autofluorescence imaging identifies tumor cell-cycle status on a single-cell level. J Biophotonics 11:
Liu, Qi; Wang, Jing; Zhao, Yue et al. (2017) Identification of active miRNA promoters from nuclear run-on RNA sequencing. Nucleic Acids Res 45:e121
Parang, B; Bradley, A M; Mittal, M K et al. (2016) Myeloid translocation genes differentially regulate colorectal cancer programs. Oncogene 35:6341-6349
Zhao, Yue; Liu, Qi; Acharya, Pankaj et al. (2016) High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML. Cell Rep 16:2003-16
Adams, Clare M; Hiebert, Scott W; Eischen, Christine M (2016) Myc Induces miRNA-Mediated Apoptosis in Response to HDAC Inhibition in Hematologic Malignancies. Cancer Res 76:736-48
Poindexter, Shenika V; Reddy, Vishruth K; Mittal, Mukul K et al. (2015) Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury. Am J Physiol Gastrointest Liver Physiol 308:G562-71
Parang, Bobak; Rosenblatt, Daniel; Williams, Amanda D et al. (2015) The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation. FASEB J 29:786-95
Ghosh, Hiyaa S; Ceribelli, Michele; Matos, Ines et al. (2014) ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. J Exp Med 211:1623-35