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.
Bibliographical noteFunding Information:
We thank George Thomas and Sara C. Kozma (IDIBELL and University of Cincinnati) for the S6K1 knockout mice and Wook Kim (Ajou University) for the cell lines. This work was financially supported through grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2012R1A5A2A28671860, 2017R1A2B3002186, and 2017R1A6A3A04001986).
We thank George Thomas and Sara C. Kozma (IDIBELL and University of Cincinnati) for the S6K1 knockout mice and Wook Kim (Ajou University) for the cell lines. This work was financially supported through grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2012R1A5A2A 28671860, 2017R1A2 B3002186, and 2017R1A6A3A04001986).
National Research Foundation of Korea, Grant numbers: 2012R1A5A2A28671860, 2017R1A2B3002186, 2017R1A6A3A04001986
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology