The Contribution of Transcriptional Coregulators in the Maintenance of β-cell Function and Identity

Abstract

Islet β-cell dysfunction that leads to impaired insulin secretion is a principal source of pathology of diabetes. In type 2 diabetes, this breakdown in β-cell health is associated with compromised islet-enriched transcription factor (TF) activity that disrupts gene expression programs essential for cell function and identity. TF activity is modulated by recruited coregulators that govern activation and/or repression of target gene expression, thereby providing a supporting layer of control. To date, over 350 coregulators have been discovered that coordinate nucleosome rearrangements, modify histones, and physically bridge general transcriptional machinery to recruited TFs; however, relatively few have been attributed to β-cell function. Here, we will describe recent findings on those coregulators with direct roles in maintaining islet β-cell health and identity and discuss how disruption of coregulator activity is associated with diabetes pathogenesis.

Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells

“…Apart from affecting PDX1 abundance, conditions associated with increased ROS can affect PDX1 transcriptional activity by targeting coactivator complexes associated with PDX1 ( 97 ). For example, decreased interaction between PDX1 and the chromodomain helicase DNA-binding 4 (CHD4) ATPase subunit of the NuRD complex is observed in both islets of type-2 donors and in mice fed on HFD ( 83 ).…”

The Ldb1 transcriptional co‐regulator is required for establishment and maintenance of the pancreatic endocrine lineage

“…24,25 Despite extensive characterization of TFs in the pancreas, only a small handful of transcriptional co-regulators have been identified and explored in the islet, and even fewer during cell fate specification. 26,27 The Swi/Snf chromatin remodeling complex directly associates with Pdx1 during organogenesis and onward, with disruption of this interaction causing glucose intolerance and impaired insulin secretion. 28 The Set7/9 histone methyltransferase is enriched in islets and interacts with Pdx1, also allowing for the maintenance of Pdx1 activity in βcells.…”