S6K1 controls epigenetic plasticity for the expression of pancreatic α/β cell marker genes

Abstract

The failure of insulin production by pancreatic β cells is a common hallmark of type 1 diabetes mellitus (T1DM). Because administration of exogenous insulin is associated with diabetes-derived complications, endogenous α to β cell transition can be an attractive alternative. Although decreased β cell size and hypoinsulinaemia have been observed in S6K1-deficient mice, the molecular mechanism underlying the involvement of S6K1 in the transcriptional regulation of insulin remains elusive. Here, we show that the hypoinsulinaemic phenotype of S6K1-deficient mice stems from the dysregulated transcription of a set of genes required for insulin and glucagon production. First, we observed that increased expression of α cell marker genes and decreased expression of β cell marker genes in pancreas tissues from S6K1-deficient mice. Furthermore, S6K1 was highly activated in murine β cell line, βTC6, compared to murine α cell line αTC1. In both α and β cells, active S6K1 promoted the transcription of β cell marker genes, including insulin, whereas S6K1 inhibition increased the transcription of α cell marker genes. Moreover, S6K1 mediated pancreatic gene regulation by modifying two histone marks (activating H3K4me3 and repressing H3K27me3) on gene promoters. These results suggest that S6K1 drives the α to β transition through the epigenetic regulation of cell-specific genes, including insulin and glucagon. This novel role of S6K1 in islet cells provides basic clues to establish therapeutic strategies against T1DM.

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

“…While insulin-secreting β-cells and glucagon-secreting α-cells have different physiological functions, a study revealed that human α, β, and exocrine cells share similar profiles of histone methylation of H3K4me3 and H3K27me3, suggesting an epigenomic plasticity of islet cells and their reprogrammable potentials to treat diabetes (Bramswig et al, 2013). For example, the activation of the S6K1 kinase promotes α to β-cell transition by activating β-cell genes while repressing α-cell genes through histone methylation of the activating H3K4me3 and repressing H3K27me3, respectively (Yi et al, 2018). Human pancreatic α-cells can also be reprogrammed into insulin-producing cells by PDX1, and when transplanted, can treat diabetic mice (Furuyama et al, 2019).…”

Beyond controlling cell size: functional analyses of S6K in tumorigenesis

“…In contrast, adipose tissue of mice depleted with S6k1 shows lower levels of pS36 H2B and H3K27me3 [ 181 ], highlighting strategies to employ specific S6K1 inhibitors to suppress obesity and overcome insulin resistance, bypassing mTORC2 inhibition. In islet cells, S6K1 is capable of promoting H3K4me3 and inhibiting H3K27me3 to support transcription marker genes of β cells and suppress those of α cells [ 182 ]. It is believed that the pancreatic cell transition induced by S6K1 might provide basic clues for type I diabetes.…”