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

Abstract

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 β-cell function. In the current 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 δ-cell number is increased in Insm1delSNAG but not in Insm1 null mutants as compared with the control mice. We also show a less severe reduction of the β-cell number in Insm1delSNAG as that in Insm1 null mutants. In addition, similar deficits are observed in α-, PP, and ε-cells in Insm1delSNAG and Insm1 null mutants. We further identified that the increased δ-cell number is due to β- to δ-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 hematopoietically expressed homeobox (Hhex) loci that are bound by Insm1, thereby promoting the transcriptional activity of the δ-cell–specific gene Hhex. Our study has identified a novel function of the SNAG domain of Insm1 in the regulation of pancreatic endocrine cell differentiation, particularly in the repression of β- to δ-cell transdifferentiation.

Deciphering early human pancreas development at the single-cell level

“…5f ). In the trunk endocrine transition, YBX1 upregulated INSM1 , which is a key regulator in the endocrine lineage and has been reported to participate in mouse islet development and β-cell identity maintenance 52 , 53 . INSM1 , in turn, upregulated a series of genes confined to endocrine lineages, including FEV and PAX6 , which are reported to be key regulators in the development of EP cells and to trigger a complex network that sustains EP identity (Fig.…”

“…The function of HDAC in EP cell differentiation in the human pancreas still needs to be validated. Moreover, in a combined analysis with scATAC-seq data, we identified TFs in trunk cells governing cell fate choice in endocrinogenesis; these TFs included YBX1 , which upregulated INSM1 , a reported important regulator in mouse islet development 52 , 53 , to favor endocrine lineage differentiation. Our data suggested that ID4 , which upregulated HES4 in trunk cells, could suppress endocrine differentiation and favor ductal lineage development.…”

The Haematopoietically-expressed homeobox transcription factor: roles in development, physiology and disease

“…Moreover, decreased somatostatin in Hhex KO pancreatic islets caused impaired paracrine inhibition of insulin released from beta cells (137). In beta cells the Hhex locus is targeted by Lsd1 which facilitates H3K3me1/2 methylationmediated repression of Hhex preventing beta to delta cell transition (Figure 3) (138). This suggested that compromised paracrine control may be partly responsible for T2D through the acceleration of beta cell exhaustion and failure (137).…”

Mechanisms and Physiological Roles of Polymorphisms in Gestational Diabetes Mellitus

“…Notably, HHEX was not detected in the pancreatic β-cells and α-cells of adult humans and mice, while it was exhibited in adult pancreatic δ-cells and regulated somatostatin secretion [30]. Lysine-specific demethylase-1 targeted the Hhex locus and promoted the repression of Hhex by facilitating methylation at H3K4me1/2, leading to the prevention of the transition of β-cells to δ-cells [31].…”