Reduced functional β-cell mass is a hallmark of Type 2 Diabetes (T2D). Replenishing the β-cell pool in the setting of insulin resistance or obesity can increase insulin levels sufficiently to counteract T2D, a goal hampered by decreased β-cell proliferative potential with age. Therefore, an exciting goal for the treatment of T2D is to simultaneously increase proliferation while maintaining function. FoxM1, a forkhead box transcription factor known for its critical role in promoting cell cycle progression, is necessary for β-cell proliferation in multiple settings. I derived a transgenic mouse inducibly expressing activated FoxM1 in β-cells and demonstrated that activated FoxM1 enhances glucose-stimulated insulin secretion (GSIS) in male but not female mice. Islets from male mice lacking FoxM1 in β-cells (Foxm1Δβ mice) display attenuated glucose-stimulated insulin secretion, indicating that FoxM1 is a nodal protein regulating the β-cell transition from optimal function to replication (Figure A). Thus, FoxM1 represents a powerful target for T2D therapy. One project in my lab will be to test the hypothesis that FoxM1 directly regulates genes promoting GSIS and explore the mechanisms by which FoxM1 distinguishes functional from cell cycle targets.
I will explore the relationship between FoxM1 and the estrogen receptor α (ERα) since they have been shown to be cooperative binding partners in several cell types and since ERα may mediate the differences observed between male and female mice expressing activated FoxM1. To determine if FoxM1 and ERα are cooperative binding partners, microfluidics-based oscillatory washing (MOW)ChIP will be applied to sorted proliferating and quiescent β-cells from both male and female islets. The role of ERα during FoxM1-mediated enhanced insulin secretion will be examined using genetic and pharmacological inhibition of estrogen signaling. RNA-Seq on β-cells FACS-sorted from wild-type and FoxM1-deficient islets will be employed to identify functional targets of FoxM1.
Finally, to explore how FoxM1 distinguishes between proliferative targets, which are expressed in all tissues, and β-cell-specific functional targets de novo motif will be used to mine the MOW-ChIP data, described above.
Kameswaran, Vasumathi; Golson, Maria; Rodriguez, Mireia; Ou, Kristy; Wang, Yue; Zhang, Jia; Pasquali, Lorenzo; Kaestner, Klaus: The dysregulation of the DLK1-MEG3 locus in islets from type 2 diabetics is mimicked by targeted epimutation of its promoter with TALE-DNMT constructs. Diabetes 2018.
Golson ML and Kaestner KH: Epigenetics in formation, function, and failure of the endocrine pancreas. Molecular Metabolism May 2017.
Bernstein D, Golson ML, Kaestner KH.: Epigenetic control of β-cell function and failure. Diabetes Res Clin Pract 123: 24-36, January 2017.
Golson ML and Kaestner KH: Fox transcription factors: from development to disease. Development 143(24): 4558-4570, December 2016.
Wang YJ, Schug J, Won KJ, Liu C, Naji A, Avrahami D*, Golson ML*, and Kaestner KH*: Single-Cell Transcriptomics of the Human Endocrine Pancreas. Diabetes 65(10): 3028-38, October 2016.
Wang YJ, Maria L. Golson ML, Schug J, Traum D, Liu C, Vivek K, Dorrell C, Naji A, Powers AC, Chang KM, : Single-Cell Mass Cytometry of the Human Endocrine Pancreas. Cell Metabolism 24(4): 616-626, October 2016.
Aoki R, Shoshkes-Carmel M, Gao N, Shin S, May CL, Golson ML, Zahm AM, Ray M, Wiser CL, Wright CV, Kaestner KH.: Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol 2(2): 175-188, February 2016.
Golson, M. L., Dunn, J. C., Maulis, M. F., Dadi, P. K., Osipovich, A. B., Magnuson, M. A., Jacobson, D. A., Gannon, M.: Activation of FoxM1 revitalizes the replicative potential of aged beta -cells in male mice and enhances insulin secretion. Diabetes 64(11): 3829-3838, November 2015.
Golson, M. L., Bush, W. S., Brissova, M.: Automated quantification of pancreatic beta-cell mass. Am J Physiol Endocrinol Metab 306(12): E1460-7, 2014.
Golson, M. L., Maulis, M. F., Dunn, J. C., Poffenberger, G., Schug, J., Kaestner, K. H., Gannon, M. A.: Activated FoxM1 attenuates streptozotocin-mediated beta-cell death. Mol Endocrinol 28(9): 1435-47, 2014.
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Last updated: 07/05/2018
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