Scrt1, a transcriptional regulator of \u03b2-cell proliferation identified by differential chromatin accessibility during islet maturation

Jonathan Sobel,Romano Regazzi,Ofer Elhanani,Michael D Walker,Véronique Menoud,Adriana Rodriguez-Trejo,Lisa Stoll,Cécile Jacovetti,Claudiane Guay

doi:10.1038/s41598-021-88003-2

Abstract

Glucose-induced insulin secretion, a hallmark of mature β-cells, is achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for establishing an appropriate functional β-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in functional maturation of β-cells remain to be elucidated. Here, we addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. We obtained a genome-wide picture of chromatin accessible sites (~ 100,000) among which 20% were differentially accessible during maturation. An enrichment analysis of transcription factor binding sites identified a group of transcription factors that could explain these changes. Among them, Scrt1 was found to act as a transcriptional repressor and to control β-cell proliferation. Interestingly, Scrt1 expression was controlled by the transcriptional repressor RE-1 silencing transcription factor (REST) and was increased in an in vitro reprogramming system of pancreatic exocrine cells to β-like cells. Overall, this study led to the identification of several known and unforeseen key transcriptional events occurring during β-cell maturation. These findings will help defining new strategies to induce the functional maturation of surrogate insulin-producing cells.

Highlights

Glucose-induced insulin secretion, a hallmark of mature β-cells, is achieved after birth and is preceded by a phase of intense proliferation
Using two different computational approaches to investigate potential to specific binding sites (TFBS) motifs in the regions with accessibility changes, we identified putative regulatory elements in the promoter or in distal cis-regulatory modules (CRM) of genes encoding differentially expressed mRNAs that may be implicated in islet maturation
Consistent with the data in the literature we previously observed that postnatal day 10 (P10) rat β-cells have a high proliferative capacity compared to adult mature β-cells but are unable to secrete insulin in response to g lucose[1]

Summary

Introduction

Glucose-induced insulin secretion, a hallmark of mature β-cells, is achieved after birth and is preceded by a phase of intense proliferation. Key regulators of gene expression involved in functional maturation of β-cells remain to be elucidated We addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. Can cooperate on cis-regulatory modules (CRM), which are DNA stretches of about 100–1000 bp, to produce specific regulatory e vents[14] Taking advantage of this approach, we aimed at determining how neonatal islet maturation in rat is controlled at the transcriptional level, and to identify the key transcription factors involved. Using two different computational approaches to investigate potential TFBS motifs in the regions with accessibility changes, we identified putative regulatory elements in the promoter or in distal CRM of genes encoding differentially expressed mRNAs that may be implicated in islet maturation. Scrt[1] expression was found to be controlled by the transcriptional repressor RE-1 silencing transcription factor (REST) and to increase during the course of reprogramming of pancreatic exocrine cells into β-like c ells[15]

Methods

Results

Conclusion