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PRMT1-dependent histone arginine methylation regulates mature beta cell identity (ChIP-Seq)

ABSTRACT: Purpose: Loss of functional β cell mass is an essential feature of type 2 diabetes and recent studies indicate that cell dedifferentiation can result in the loss of functional cell mass. However, the mechanism of cell dedifferentiation has not been elucidated due to the lack of appropriate animal model. Methods: Prmt1 floxed mice were crossed with Rip2-Cre and Pdx1-CreERT2 mice to generate Prmt1 KO and Prmt1 iKO mice. R26-eYFP mice were crossed for lineage tracing experiments and cell sorting. All mice were backcrossed and maintained on a C57BL/6J background. Cre recombination for CreERT2 was induced by total 5 times intraperitoneal injections (75 mg/kg) of corn oil dissolved tamoxifen (T5648, Sigma-Aldrich) over 2 weeks. Results: Deletion of Prmt1 in mature cells resulted in the immediate loss of H4R3me2a which induced cell dedifferentiation and cell selective Prmt1 knock-out mice developed diabetes phenotype. H4R3me2a worked as an active histone code that increased chromatin accessibility at the binding sites for transcription factors including CTCF, NKX6.1, MAFA, PDX1 and NEUROD1. Conclusions: PRMT1-dependent open chromatin regions showed a strong association with the risk of diabetes in human. In conclusion, PRMT1 plays an essential role in maintaining β cell identity by regulating chromatin accessibility.

ORGANISM(S): Mus musculus

PROVIDER: GSE117097 | GEO | 2020/12/03

REPOSITORIES: GEO

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Project description:Background & Aims: Metaplasia and dysplasia in the corpus are reportedly derived from dedifferentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen Ctranscript expressing cells (PGC-transcript expressing cells) represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model. Methods: We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate PgcCreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments, histological and immunofluorescence staining. We further established Pgc-CreERT2;Kras G12D/+ mice and investigated whether PGCtranscript expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC-transcript expressing cells with activated Kras, inactivated Apc and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D , Apcflox , Trp53 flox mice. Results: Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;Kras G12D/+ mice, PGC-transcript expressing cells with Kras G12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven Kras G12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+ ;Apc flox/flox mice presented intramucosal dysplasia/carcinoma, while Pgc-CreERT2;KrasG12D/+ ;Apcflox/flox ;Trp53 flox/flox mice presented invasive and metastatic gastric carcinoma. Conclusions: The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development.

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PRMT1-dependent histone arginine methylation regulates mature beta cell identity (ChIP-Seq)

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