The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses Beta- to Delta-Cell Transdifferentiation

The allocation and specification of pancreatic endocrine lineages are tightly regulated by transcription factors. Disturbances in differentiation of these lineages contribute to the development of various metabolic diseases, including diabetes. The Insulinoma-associated protein 1 (Insm1), which encodes a protein containing one SNAG domain and five zinc fingers, plays essential roles in pancreatic endocrine cell differentiation and in mature beta-cell function. In the present study, we compared the differentiation of pancreatic endocrine cells between Insm1 null and Insm1 SNAG domain mutants (Insm1delSNAG) to explore the specific function of the SNAG domain of Insm1. We show that the delta-cell number is increased in Insm1delSNAG but not in Insm1 null mutants as compared to the control mice. We also show a less severe reduction of the beta-cell number in Insm1delSNAG as that in Insm1 null mutants. In addition, similar deficits are observed in alpha-, PP- and epsilon-cell in Insm1delSNAG and Insm1 null mutants. We further identified that the increased delta-cell number is due to beta- to delta-cell transdifferentiation. Mechanistically, the SNAG domain of Insm1 interacts with Lsd1, the demethylase of H3K4me1/2. Mutation in the SNAG domain of Insm1 results in impaired recruitment of Lsd1 and increased H3K4me1/2 levels at Hhex loci that are bound by Insm1, thereby promoting the transcriptional activity of the delta-cell-specific gene Hhex. Our study has identified a novel function of the SNAG domain of Insm1 in the regulation of pancreatic endocrine cells differentiation, particularly in the repression of beta- to delta-cell transdifferentiation.