By Lorena Infante Lara
Research from the labs of Roland Stein (Molecular Physiology & Biophysics) and Chris Wright (Cell & Developmental Biology) suggests that the chromatin remodeling complex Swi/Snf, when bound to transcription factor Pdx1, is required for controlling the growth rate of the embryonic pancreas and for maintaining β cell identity in the adult organ.
Our bodies depend on the interplay of pancreatic hormones to regulate blood sugar levels. Key to this interplay are the glucagon-secreting α cells and insulin-secreting β cells that reside in the pancreatic islets of Langerhans. β cells are associated with type 1 diabetes, which occurs when the cells are destroyed, and type 2 diabetes, caused by insulin resistance and a failure of the β cells to function properly. In both conditions, inadequate insulin signaling results in an inability to decrease blood sugar levels, accompanied by other metabolic abnormalities that ultimately lead to considerable morbidity and/or mortality.
Prior research suggests that the size of the pancreas influences a person’s susceptibility to diabetes, so it is essential to identify the determinants of pancreas size. For their paper, published in the journal Diabetes, Stein and Wright looked at the pancreatic and duodenal homeobox 1 (Pdx1) transcription factor that is critical for the development of the pancreas and for repressing α cell functional genes in β cells.
Transcription factors often effect their gene regulatory actions through the recruitment of coregulators. In a prior study, Swi/Snf was found to associate with Pdx1, and Pdx1 was determined to be the principal β cell-enriched transcription factor bound to Swi/Snf in mouse β cells. Therefore, the authors of this study investigated how the Pdx1:Swi/Snf complex affects the growth rate of the embryonic pancreas and helps to maintain β cell identity in the adult.
To begin, the authors found that Pdx1 binds to the Brg1 and Brm1 subunits of the Swi/Snf complex and that knocking out Brg1 (but not Brm1) in embryos results in a smaller pool of β cell progenitors. Interestingly, the pool of progenitor cells, termed multipotent pancreatic cells (MPCs), was smaller due to a reduced ability to proliferate and not to cell death. In the adult pancreas, however, removal of both Brg1 and Brm1 was necessary to see an impairment in β cell function. These Brg1/Brm1 double-knockout (DKO) mice suffered from fasting hyperglycemia, glucose intolerance, and reduced serum insulin levels, symptoms that are characteristic of type 1 diabetes. Consistently, insulin production was depleted in DKO mice, even though many important transcription factors enriched in β cells were unaffected. An interesting feature of the DKO β cells was that they showed impaired expression of Pdx1-dependent genes that are essential for maintaining β cell identity. Critically, binding of Pdx1 to the enhancer of Ins2 (one of the two insulin genes in mice) was decreased when Brg1 and Brm1 were knocked down.
Despite prior genome-wide association studies (GWAS), the Swi/Snf complex had not yet been directly associated with the pathogenesis of diabetes. Stein and Wright’s research provides mechanistic information for how Pdx1 and the Swi/Snf complex interact during development to generate a healthy MPC pool size, which is of vital importance considering that a small pancreas size is a global physical determinant linked to susceptibility to type 1 and type 2 diabetes. Their work also points to how the Swi/Snf complex and Pdx1 help regulate the expression of genes that are critical for β cell function and identity. Clarity in the key role that the chromatin remodeling complex and Pdx1 play raises the intriguing possibility of targeting their interaction as a therapeutic treatment against type 2 diabetes.