Tet2 Controls β cells Responses to Inflammation in Type 1 Diabetes

Abstract

Abstractβ cells may participate and contribute to their own demise during Type 1 diabetes (T1D). We identified a novel role of Tet2 in regulating immune killing of β cells. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO β cells show reduced expression of inflammatory genes, associated with closed transcription factor binding sites. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells. We conclude that Tet2 regulates pathologic interactions between β cells and immune cells and controls intrinsic protective pathways. Modulating TET2 may enable survival of β cells or their replacements in the setting of pathologic immune cells.

Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation

“…GADD45 is highly expressed in beta cells (18), thus, further studies are necessary to investigate the involvement of GADD45 and other co-factors in recruiting Tet1 to the CTSH locus to maintain its transcriptional activation. Our results are different than those reported by Rui et al, who found that cytokines IL-1 + TNF- + IFN- increased the transcription of DNMT3A and Tet2 in human islets (35,36) while we did not. The differences could be due to the different cytokine concentrations used in ex vivo culture.…”

“…Our results are different than those reported by Rui et al . ( 35 , 36 ), who found that cytokines IL-1β + TNF-α + IFN-γ increased the transcription of DNMT3A and Tet2 in human islets, whereas we did not. The differences could be due to the different cytokine concentrations used in ex vivo culture.…”

DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis

“…Recent data shows that an inflammatory milieu can alter DNA methylation in human islets via TET2 dependent DNA demethylation, concomitant with increased expression of inflammatory and immune pathways genes (175). In line with this, emerging evidence suggests that Tet2 may regulate beta cell response to inflammation in T1D (176). Future studies in islets from auto-antibody positive, nondiabetic cases as well as T1D with residual beta cells in the pancreas may help determine if islet DNA methylation patterns are altered in human islet autoimmunity, and whether they directly contribute to beta cell dysfunction and cell-death in T1D.…”