David Keller Ph.D. 2002 Oregon Health & Science University Assistant Professor, Dept. of Biological Sciences California State University, Chico 530-898-5040 dmkeller@csuchico.edu Classes: Bio 411 Cell Biology
Research: My lab is interested in the molecular and genetic mechanisms of organ and tissue identity. In multicellular organisms, each cell in the body has the exact same copy of the genome, and yet it is readily apparent that the organs of the body are structurally diverse and functionally specialized. What is the genetic basis for this specialization? The answer is that each cell expresses only a subset of all the genes in the genome. Only those genes necessary for that particular cell are expressed, and no others. The process of expressing genes is called transcription and involves the generation of messenger RNA from a DNA template. Transcription is controlled by protein transcription factors and by small regulatory RNA molecules called microRNAs. Whereas some transcription factors and microRNAs are broadly distributed throughout the body, others are restricted to only one organ or tissue. These regulatory molecules are called cellular identify factors, because they impart identity to the cell based upon the genes they turn on (or off). My lab uses molecular and cellular techniques to study cellular identity factors that control development and homeostasis of pancreatic beta cells, the endocrine cells that secrete the hormone insulin after a meal. One protein transcription factor we study is Pdx-1, a factor critical for early pancreatic development as well as maintenance of the beta cell phenotype. Patients with mutations in Pdx-1 develop a form of the disease diabetes mellitus, due to the deficiency of insulin production. My lab also studies a predominantly beta cell microRNA called miR-375. Studies suggest that animals lacking miR-375 develop abnormal Islets of Langerhans, the endocrine cells of the pancreas, which includes the beta cells. In mature beta cells, miR-375 appears to regulate insulin secretion. The similar roles of Pdx-1 and miR-375 have led us to investigate how they may be interlinked. Recent articles: 1. Keller, D.M., McWeeney, S., Arsenlis, A., Drouin, J., Wright, C.V.E., Wang, H, Wollheim, C.B.,White, P., Kaestner, K., and Goodman, R.H. (2007). Characterization of pancreatic transcription factor Pdx-1 binding sites using promoter microarray and serial analysis of chromatin occupancy. J. Biol. Chem. 282: 32084-32092. 2. Vo, N., Klein, M.E., Varlamova, O., Keller, D.M., Yamamoto, T., Goodman, R.H., and Impey, S. (2005). A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl. Acad. Sci. USA. 102: 16426-31. 3. Cha-Molstead, H., Keller, D.M., Yochum, G.S., Impey, S., and Goodman, R.H. (2004). Cell-type-specific binding of the transcription factor CREB to the cAMP-resonse element. Proc. Natl. Acad. Sci. USA. 101: 13572-13577.		Mouse insulinoma MIN6 cells stained with a fluorescent insulin antibody, revealing the polarized secretory macherinery of pancreatic beta cells.
		Diagram of a feed-forward transcriptional network in pancreatic beta cells in which Pdx-1 controls the expression of the insulin gene as well as the expression of transcription factors. This type of network can promote long-term activation of the target genes.
		A proposed multi-component loop in which Pdx-1 activates the expression of the transcription factor Pax6, and vice versa. This type of transcriptional network stabilizes the expression of each factor.
		A diagram showing a gene regulatory network involving transcription factors and microRNA that functions to control pancreatic beta cell development and insulin release. It is unclear how Pdx-1 and NeuroD1 regulate miR-375 at this time.