The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses β- to δ-Cell Transdifferentiation

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