Tcf19 Knockout Mouse Islets Have Increased Stress‐related Gene Expression and Reduced Proliferative Capacity

Abstract

Transcription factor 19 (Tcf19) is a putative transcription factor associated with both Type 1 and Type 2 diabetes. Tcf19 is expressed in human and rodent pancreatic β‐cells and is upregulated in proliferating islets and obesity. We generated a whole body knockout (wbKO) of Tcf19 and the resulting lean, 15‐week‐old mice have normal fasting glucose, insulin secretion, and glucose tolerance compared to control. RNASeq led to the identification of 733 upregulated and 763 downregulated genes in wbKO islets compared to control. Overrepresented GO terms include upregulated apoptotic process, and negative regulation of cell proliferation, and downregulated vesicle‐mediated transport. We verified markers of proliferation, β‐cell identity, cell stress, and pro‐apoptosis using RTqPCR. Ki67, Pdx1, Nkx6.1, and Nkx2.2 were significantly decreased while Chop, Bak, Gadd45α, and Dtx3l were significantly increased in islets from wbKO mice. Whole pancreas was harvested to measure β‐cell area and although total area is not different, wbKO mice have altered islet size distribution with an increased number of small islets. Next, β‐cell proliferation and apoptosis were measured in frozen pancreatic sections using Ki67 and TUNEL staining, which revealed significantly less proliferation with no change in apoptosis rates in wbKO mice. In adulthood, β‐cell mass expansion occurs due to proliferation as an early compensation for insulin resistance in response to obesity. To determine the role of Tcf19 in this adaptive response wbKO and control mice were put on a one‐week high fat diet (HFD). After one week on HFD, islets from wbKO do not appropriately upregulate Ki67 and cyclin D2 as measured by RTqPCR. In summary, Tcf19 is involved in proliferation and stress related processes both of which are involved in regulating β‐cell mass, which declines in Type 1 and Type 2 diabetes. Support or Funding Information VA Merit Award 1I01BX001880VA Merit Award 1I01BX004715TL1 Award TR000429ICTR Clinical and Translational Science Award UL1TR000427NIDDK 5R01DK110324

Whole Genome Sequencing Reveals Multiple Linked Genetic Variants on Canine Chromosome 12 Associated with Risk for Symmetrical Lupoid Onychodystrophy (SLO) in the Bearded Collie

“…The two frameshift variants in TCF19 (novel variants: p.Gln114fs and p.Trp164fs), leading to significant amino acid changes in the first fourth of the protein as well as a premature stop codon, were strongly associated with SLO and also in strong LD with the TNXB, LTB, and GPSM3 variants. The TCF19 gene encodes a transcription factor involved in regulating cell proliferation and differentiation and has been implicated in type 1 diabetes where it appears to act as a regulator of β-cell mass in the pancreas [65,66]. Despite its association with another organ-specific autoimmune disorder, there is no other evidence in the literature to connect this gene's function to SLO development.…”