In eukaryotes, gene regulation is largely controlled at the transcriptional level by promoter-specific activator proteins (activators) whose DNA binding sites are typically present upstream of the core promoter of genes transcribed by RNA polymerase II (class II genes). Activators must work, directly or indirectly, through a set of general transcription factors (GTFs) that are required for transcription of all class II genes. The mechanisms by which activators stimulate transcription is the subject of this application. A variety of studies have shown that activators function at least in part by stimulating pre- initiation complex (PIC) assembly. During the past funding period we have shown how the chromatin immunoprecipitation (CHIP) assay can be used to study PIC assembly in living cells. We will continue to use this assay to study activator-mediated PIC assembly in yeast and higher eukaryotes. We have also made significant progress in our understanding of the role of TBP- Associated-Factors (TAFIIS). We will continue and extend our systematic investigation of how individual TAFIIS mediate transcriptional activation and cell cycle progression. Previous studies from our laboratory and others have implicated the GTF TFIIB in the mechanism by which some activators function. Experiments are proposed to continue to study the role of TFIIB in transcription actiation in vivo. Finally, our experience with the CHIP assay has suggested an approach for developing a general method for identifying the gene targets of activators. Such a method would be extremely useful in many areas of biology and medicine.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Tompkins, Laurie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Fang, Minggang; Hutchinson, Lloyd; Deng, April et al. (2016) Common BRAF(V600E)-directed pathway mediates widespread epigenetic silencing in colorectal cancer and melanoma. Proc Natl Acad Sci U S A 113:1250-5
Pedanou, Victoria E; Gobeil, Stéphane; Tabariès, Sébastien et al. (2016) The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L. Elife 5:
Nagarajan, Arvindhan; Petersen, Max C; Nasiri, Ali R et al. (2016) MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nat Commun 7:12639
Sellars, MacLean; Huh, Jun R; Day, Kenneth et al. (2015) Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages. Nat Immunol 16:746-54
Fang, Minggang; Pak, Magnolia L; Chamberlain, Lynn et al. (2015) The CREB Coactivator CRTC2 Is a Lymphoma Tumor Suppressor that Preserves Genome Integrity through Transcription of DNA Mismatch Repair Genes. Cell Rep 11:1350-7
Bhatnagar, Sanchita; Zhu, Xiaochun; Ou, Jianhong et al. (2014) Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Proc Natl Acad Sci U S A 111:12591-8
Bhatnagar, Sanchita; Gazin, Claude; Chamberlain, Lynn et al. (2014) TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature 516:116-20
Fang, Minggang; Ou, Jianhong; Hutchinson, Lloyd et al. (2014) The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype. Mol Cell 55:904-915
Nagarajan, Arvindhan; Dogra, Shaillay Kumar; Liu, Alex Y et al. (2014) PEA15 regulates the DNA damage-induced cell cycle checkpoint and oncogene-directed transformation. Mol Cell Biol 34:2264-82
Forloni, Matteo; Dogra, Shaillay Kumar; Dong, Yuying et al. (2014) miR-146a promotes the initiation and progression of melanoma by activating Notch signaling. Elife 3:e01460

Showing the most recent 10 out of 27 publications