BADERC Welcome

Melissa Thomas, M.D., Ph.D.

Transcriptional regulation of pancreatic beta-cell growth and survival

The research program in the Thomas laboratory is focused on the transcriptional regulation of insulin production and pancreatic beta-cell proliferation and apoptosis in cellular and mouse models of diabetes. Emerging evidence from large genome-wide association studies in individuals with type 2 diabetes implicates regulators of pancreatic beta-cell mass and insulin production as important contributors to heritable risk for the development of diabetes. A better understanding of regulatory signals that govern expansion of endogenous beta-cell mass will support efforts to restore insulin production in diabetes. These studies are focused on the identification of novel regulatory mechanisms that govern the maintenance and expansion of adult beta-cell mass and function.

1) Coactivator-mediated regulation of pancreatic beta-cell mass: Dr. Thomas discovered and studies the coactivator Bridge-1 and its functions in the regulation of insulin gene expression, glucose homeostasis, and beta-cell survival. The laboratory is defining molecular mechanisms by which Bridge-1 regulates both cellular survival and proliferation in mouse and cellular models. Her recent studies implicate the coactivator in the transcriptional regulation of expression of anti-apoptotic regulators important for pancreatic beta-cell survival and of G1/S cell cycle checkpoint regulators essential for maintaining pancreatic beta-cell mass. Her laboratory investigates conserved metabolic regulatory functions of the C. elegans homologue of Bridge-1 in collaborative studies. With a translational award from the Partners Center for Drug Discovery, her research team is developing a small-molecule screening program to identify Bridge-1-dependent regulators of pancreatic beta-cell survival.

2) Age-dependent changes in pancreatic beta-cell function: The Thomas laboratory has investigated age-dependent changes in regulation of the pdx-1 gene and identified functionally important acquired pancreatic islet cell signaling defects. Expression levels of the MODY4 transcription factor PDX-1 decline in mouse and human islet cells with aging, a reflection of selective age-dependent changes in transcriptional programming. The laboratory has identified a subset of pdx-1 promoter regulators with age-dependent changes in temporal expression patterns and functional changes in chromatin occupancy of promoter regulatory sequences in mouse pancreatic islets. Dr. Thomas has implicated the glucose and growth factor sensor Egr-1 in the regulation of insulin production, PDX-1 expression, and beta-cell proliferation. The laboratory is testing a model that acquired Egr-1 deficiency with aging disrupts a transcriptional regulatory network to impair beta-cell sensing of mitogenic signals and reduce beta-cell proliferative capacity.

3) Adaptive expansion of pancreatic beta-cell mass in response to obesity: The essential driving signals for expansion of pancreatic beta-cell mass in response to increased metabolic demand are yet to be identified. The Thomas laboratory is characterizing temporal progression of pancreatic islet gene expression patterns in response to high fat diet and integrating observed changes in pancreatic islet signaling with metabolic and pancreatic beta-cell mass phenotypes. These studies are designed to identify endogenous pathways that govern adaptive increases in pancreatic beta-cell mass and represent novel targets for the restoration of insulin production in diabetes. Mechanisms for adaptive expansion of beta-cell mass under investigation include identification of nutrient-responsive autocrine/paracrine regulators of beta-cell replication and of activators of beta-cell differentiation programs.

4) Regulation of pancreatic beta-cell regeneration by the diabetes gene TCF7L2: The mechanisms by which noncoding polymorphisms in the human diabetes gene TCF7L2 contribute to the pathogenesis of Type 2 diabetes are unknown, but clinical studies indicate that these polymorphisms impair pancreatic beta-cell function and insulin secretion. To better define the functions of TCF7L2 within the endocrine pancreas, the Thomas laboratory is characterizing pancreatic and metabolic phenotypes of TCF7L2-deficient mice. The laboratory is testing the hypothesis that TCF7L2 deficiency restricts the capacity to expand pancreatic beta-cell mass in response to metabolic or hormonal signals.

References:

Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. Endocrinology 2004, 145: 918-28.
Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the HNF1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology 2004, 145:3941-3949.
Gragnoli C, Stanojevic V, Gorini A, von Preussenthal M, Thomas MK, Habener JF. IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabolism 2005, 54:983-8.
Stanojevic V, Yao KM, Thomas MK. The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1). Mol Cell Endocrinol 2005, 237:67-74.
Lee JH, Volinic JV, Banz C, Yao KM, Thomas MK. Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1. J Endocrinol 2005, 187: 283-92.
Volinic JL, Lee JH, Eto K, Kaur V, Thomas MK. Overexpression of the coactivator Bridge-1 results in insulin deficiency and diabetes. Mol Endocrinol 2006, 20: 167-82.
Eto K, Kaur V, Thomas MK. Regulation of insulin gene transcription by the immediate early response ,gene Egr-1. Endocrinology 2006, 147:2923-35.
Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch K, Thomas MK, Schneyer AL. FSTL3 deletion reveals roles for TGFb family ligands in glucose and fat homeostasis in adults. Proc Natl Acad Sci 2007, 104:1348-53.
Yano T, Liu Z, Donovan J, Thomas MK, Habener JF. Stromal cell-derived factor-1 (SDF-1/CXCL12) attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt. Diabetes 2007, 56:2946-57.
Eto K, Kaur V, Thomas MK. Regulation of pancreas duodenum homeobox-1 expression by early growth response-1. J Biol Chem 2007, 282:5973-83.

Reviews and Chapters

Thomas MK, Habener JF. IDX-1: Pancreatic agenesis and Type 2 diabetes. In Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular basis of inborn errors of development. Oxford Univ. Press 2004, p. 552-556.
Habener JF, Kemp DM, Thomas MK. Transcriptional regulation in pancreatic development. Endocrinology 2005; 146:1025-1034.
Thomas MK, Habener JF. PDX-1 and pancreatic agenesis and type 2 diabetes. In Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular basis of inborn errors of development. Oxford Univ. Press 2008.
Thomas MK, Tsang SW, Yeung ML, Leung PS, Yao KM. The roles of PDZ-containing proteins Bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass. Curr Protein Pept Sci 2009, 10:30-6.






			Melissa Thomas, M.D., Ph.D. Transcriptional regulation of pancreatic beta-cell growth and survival The research program in the Thomas laboratory is focused on the transcriptional regulation of insulin production and pancreatic beta-cell proliferation and apoptosis in cellular and mouse models of diabetes. Emerging evidence from large genome-wide association studies in individuals with type 2 diabetes implicates regulators of pancreatic beta-cell mass and insulin production as important contributors to heritable risk for the development of diabetes. A better understanding of regulatory signals that govern expansion of endogenous beta-cell mass will support efforts to restore insulin production in diabetes. These studies are focused on the identification of novel regulatory mechanisms that govern the maintenance and expansion of adult beta-cell mass and function. 1) Coactivator-mediated regulation of pancreatic beta-cell mass: Dr. Thomas discovered and studies the coactivator Bridge-1 and its functions in the regulation of insulin gene expression, glucose homeostasis, and beta-cell survival. The laboratory is defining molecular mechanisms by which Bridge-1 regulates both cellular survival and proliferation in mouse and cellular models. Her recent studies implicate the coactivator in the transcriptional regulation of expression of anti-apoptotic regulators important for pancreatic beta-cell survival and of G1/S cell cycle checkpoint regulators essential for maintaining pancreatic beta-cell mass. Her laboratory investigates conserved metabolic regulatory functions of the C. elegans homologue of Bridge-1 in collaborative studies. With a translational award from the Partners Center for Drug Discovery, her research team is developing a small-molecule screening program to identify Bridge-1-dependent regulators of pancreatic beta-cell survival. 2) Age-dependent changes in pancreatic beta-cell function: The Thomas laboratory has investigated age-dependent changes in regulation of the pdx-1 gene and identified functionally important acquired pancreatic islet cell signaling defects. Expression levels of the MODY4 transcription factor PDX-1 decline in mouse and human islet cells with aging, a reflection of selective age-dependent changes in transcriptional programming. The laboratory has identified a subset of pdx-1 promoter regulators with age-dependent changes in temporal expression patterns and functional changes in chromatin occupancy of promoter regulatory sequences in mouse pancreatic islets. Dr. Thomas has implicated the glucose and growth factor sensor Egr-1 in the regulation of insulin production, PDX-1 expression, and beta-cell proliferation. The laboratory is testing a model that acquired Egr-1 deficiency with aging disrupts a transcriptional regulatory network to impair beta-cell sensing of mitogenic signals and reduce beta-cell proliferative capacity. 3) Adaptive expansion of pancreatic beta-cell mass in response to obesity: The essential driving signals for expansion of pancreatic beta-cell mass in response to increased metabolic demand are yet to be identified. The Thomas laboratory is characterizing temporal progression of pancreatic islet gene expression patterns in response to high fat diet and integrating observed changes in pancreatic islet signaling with metabolic and pancreatic beta-cell mass phenotypes. These studies are designed to identify endogenous pathways that govern adaptive increases in pancreatic beta-cell mass and represent novel targets for the restoration of insulin production in diabetes. Mechanisms for adaptive expansion of beta-cell mass under investigation include identification of nutrient-responsive autocrine/paracrine regulators of beta-cell replication and of activators of beta-cell differentiation programs. 4) Regulation of pancreatic beta-cell regeneration by the diabetes gene TCF7L2: The mechanisms by which noncoding polymorphisms in the human diabetes gene TCF7L2 contribute to the pathogenesis of Type 2 diabetes are unknown, but clinical studies indicate that these polymorphisms impair pancreatic beta-cell function and insulin secretion. To better define the functions of TCF7L2 within the endocrine pancreas, the Thomas laboratory is characterizing pancreatic and metabolic phenotypes of TCF7L2-deficient mice. The laboratory is testing the hypothesis that TCF7L2 deficiency restricts the capacity to expand pancreatic beta-cell mass in response to metabolic or hormonal signals. References: Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. Endocrinology 2004, 145: 918-28. Wang L, Coffinier C, Thomas MK, Gresh L, Eddu G, Manor T, Levitsky LL, Yaniv M, Rhoads DB. Selective deletion of the HNF1b (MODY5) gene in b cells leads to altered gene expression and defective insulin release. Endocrinology 2004, 145:3941-3949. Gragnoli C, Stanojevic V, Gorini A, von Preussenthal M, Thomas MK, Habener JF. IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabolism 2005, 54:983-8. Stanojevic V, Yao KM, Thomas MK. The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1). Mol Cell Endocrinol 2005, 237:67-74. Lee JH, Volinic JV, Banz C, Yao KM, Thomas MK. Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1. J Endocrinol 2005, 187: 283-92. Volinic JL, Lee JH, Eto K, Kaur V, Thomas MK. Overexpression of the coactivator Bridge-1 results in insulin deficiency and diabetes. Mol Endocrinol 2006, 20: 167-82. Eto K, Kaur V, Thomas MK. Regulation of insulin gene transcription by the immediate early response ,gene Egr-1. Endocrinology 2006, 147:2923-35. Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch K, Thomas MK, Schneyer AL. FSTL3 deletion reveals roles for TGFb family ligands in glucose and fat homeostasis in adults. Proc Natl Acad Sci 2007, 104:1348-53. Yano T, Liu Z, Donovan J, Thomas MK, Habener JF. Stromal cell-derived factor-1 (SDF-1/CXCL12) attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt. Diabetes 2007, 56:2946-57. Eto K, Kaur V, Thomas MK. Regulation of pancreas duodenum homeobox-1 expression by early growth response-1. J Biol Chem 2007, 282:5973-83. Reviews and Chapters Thomas MK, Habener JF. IDX-1: Pancreatic agenesis and Type 2 diabetes. In Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular basis of inborn errors of development. Oxford Univ. Press 2004, p. 552-556. Habener JF, Kemp DM, Thomas MK. Transcriptional regulation in pancreatic development. Endocrinology 2005; 146:1025-1034. Thomas MK, Habener JF. PDX-1 and pancreatic agenesis and type 2 diabetes. In Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular basis of inborn errors of development. Oxford Univ. Press 2008. Thomas MK, Tsang SW, Yeung ML, Leung PS, Yao KM. The roles of PDZ-containing proteins Bridge-1 and PDZD2 in the regulation of insulin production and pancreatic beta-cell mass. Curr Protein Pept Sci 2009, 10:30-6.