366-OR: TCF19 Promotes Functional Beta-Cell Mass and Proliferative Capacity by Regulating DNA Damage Repair Pathways

Abstract

Transcription factor 19, TCF19, is a novel gene associated with type 1 and type 2 diabetes. We have previously shown that Tcf19 is involved in the regulation of proliferation and apoptosis in the INS1 β-cell line. To determine the role of Tcf19 in diabetes pathogenesis, we generated germline whole body Tcf19 knockout mice (wbTcf19KO). Lean wbTcf19KO mice have slightly increased fasting glucose and decreased in vivo glucose-stimulated insulin secretion. We focused on the pancreatic islet in further analysis of this model due to the high expression of Tcf19 in the mouse islet and our preliminary findings in a β-cell line. RNAseq from wbTcf19KO mouse islets identified significantly decreased expression of genes involved in maintaining β-cell identity, vesicle docking, and Ca2+ sensing (Nkx6.1, Nkx2.2, Pdx1, Sort1, Syt7). Additionally, the proliferative marker, Ki67, was downregulated by 3-fold. Similarly, with immunohistochemistry of pancreatic sections, there was a 20% decrease in Ki67+ β-cells in wbTcf19KO mice. Despite no difference in overall β-cell mass compared to control mice, wbTcf19KO mice have an altered islet size distribution with an increased quantity of small islets. In addition, wbTcf19KO mice fail to increase proliferative genes in the islet, such as cyclinD2 and Ki67, in response to a short term high fat diet (HFD). Islet RNA seq analysis also showed an upregulation of genes involved in the DNA damage pathway, inflammation, and pro apoptotic genes (Ddx60, Gadd45a, Dtx3l, Chop, Bak, Ifit1, Cxcl10). Baseline levels of DNA damage in the wbTcf19KO islets are increased, as measured by γH2AX on western blot. wbTcf19KO mouse islets also have increased DNA damage after in vivo challenge with extended HFD feeding or ex vivo after cytokine exposure. Taken together, we conclude that Tcf19 plays an important role in regulating β-cell DNA damage repair pathways to prevent apoptosis and allow proliferation. Disclosure G.H. Yang: None. J. Han: None. S. Lodh: None. J.T. Blumer: None. D. Fontaine: None. D.B. Davis: None.