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

ABSTRACT

Glucose-induced insulin secretion, a hallmark of mature ß-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 ß-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in functional maturation of ß-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 ß-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 ß-like cells. Overall, this study led to the identification of several known and unforeseen key transcriptional events occurring during ß-cell maturation. These findings will help defining new strategies to induce the functional maturation of surrogate insulin-producing cells.