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The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses Beta- to Delta-Cell Transdifferentiation
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posted on 2021-02-10, 22:44 authored by Xuehua Liang, Hualin Duan, Yahui Mao, Ulrich Koestner, Yiqiu Wei, Feng Deng, Jingshen Zhuang, Huimin Li, Cunchuan Wang, Luis R. Hernandez-Miranda, Weihua Tao, Shiqi JiaThe 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.