The overall objective of my laboratory is to define the biochemical mechanisms underlying gene regulation in the developing and mature islet 2 cell. In recent years, a greater emphasis has been placed on the role of covalent histone modifications in mammalian gene transcription, particularly how such modifications enable states of open or closed chromatin (euchromatin or heterochromatin, respectively) at specific genetic loci. The collective studies of several laboratories including our own have established that Pdx1, a master transcriptional regulator in the pancreas, controls gene expression in part through recruitment of cofactors that covalently modify histones. Dimethylated histone H3-Lys4 appears to be a crucial euchromatin marker in differentiating and mature islets. Therefore, in principle, many of the effects of Pdx1 on pancreas development and islet function could be explained by its recruitment of histone methylating cofactors. We have identified a remarkably islet-enriched cofactor, Set7/9, that appears to be responsible for dimethylated H3-Lys4 at many Pdx1 target genes. Our preliminary studies show that Set7/9 haploinsufficiency in the islet leads to impaired transcription of many Pdx1 targets and causes islet dysfunction and glucose intolerance, effectively phenocopying Pdx1 haploinsufficiency itself. Thus, the overarching hypothesis of this proposal is that Set7/9 is a chromatin-modifying cofactor that functions as an effector of Pdx1 action in the developing and mature islet. To test this hypothesis, we propose the following 3 specific aims:
Aim 1 : Determine the role of Set7/9 in directing islet cell fate and mass accrual during pancreas development.
Aim 2 : Determine the role of Set7/9 in the maintenance of normal islet function and glucose homeostasis.
Aim 3 : Determine how a transcriptional complex involving Set7/9 and Pdx1 regulates MafA gene transcription in the developing and mature 2 cell. We believe that the successful completion of these aims will identify both the role and mechanisms of a crucial chromatin-modifying cofactor in islet development and function.

Public Health Relevance

Diabetes is a disorder of insulin-producing and insulin-responsive cells that afflicts 24 million Americans, and its incidence is rising at an alarming rate. The specific goal of this grant is to investigate how genes are regulated in insulin-producing cells. Overall, this project seeks to understand how insulin-producing cells are formed and how specific genes might be used to reprogram other cell types to become insulin-producing cells for individuals with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083583-03
Application #
8245180
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sato, Sheryl M
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$287,081
Indirect Cost
$69,825
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Shih, Han; Mirmira, Raghavendra G; Lin, Chien-Chi (2015) Visible light-initiated interfacial thiol-norbornene photopolymerization for forming islet surface conformal coating. J Mater Chem B Mater Biol Med 3:170-175
Fujimaki, Kyoko; Ogihara, Takeshi; Morris, David L et al. (2015) SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell. J Biol Chem 290:16607-18
Maganti, Aarthi V; Maier, Bernhard; Tersey, Sarah A et al. (2015) Transcriptional activity of the islet β cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9. J Biol Chem 290:9812-22
Filgueiras, Luciano Ribeiro; Brandt, Stephanie L; Wang, Soujuan et al. (2015) Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes. Sci Signal 8:ra10
Tersey, Sarah A; Bolanis, Esther; Holman, Theodore R et al. (2015) Minireview: 12-Lipoxygenase and Islet β-Cell Dysfunction in Diabetes. Mol Endocrinol 29:791-800
Oh, Eunjin; Stull, Natalie D; Mirmira, Raghavendra G et al. (2014) Syntaxin 4 up-regulation increases efficiency of insulin release in pancreatic islets from humans with and without type 2 diabetes mellitus. J Clin Endocrinol Metab 99:E866-70
Mirmira, Raghavendra G (2014) Editorial: The vulnerable physician-scientist. Mol Endocrinol 28:603-6
Templin, Andrew T; Maier, Bernhard; Tersey, Sarah A et al. (2014) Maintenance of Pdx1 mRNA translation in islet β-cells during the unfolded protein response. Mol Endocrinol 28:1820-30
Maganti, Aarthi; Evans-Molina, Carmella; Mirmira, Raghavendra (2014) From immunobiology to β-cell biology: the changing perspective on type 1 diabetes. Islets 6:e28778
Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K et al. (2014) Palmitate induces mRNA translation and increases ER protein load in islet β-cells via activation of the mammalian target of rapamycin pathway. Diabetes 63:3404-15

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