The Chd4 subunit of the NuRD complex regulates Pdx1-controlled genes involved in β-cell function

in Journal of Molecular Endocrinology
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  • 1 Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
  • | 2 Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
  • | 3 Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
  • | 4 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
  • | 5 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
  • | 6 Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA

Correspondence should be addressed to J M Spaeth: jspaeth@iu.edu
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Type 2 diabetes (T2D) is associated with loss of transcription factors (TFs) from a subset of failing β-cells. Among these TFs is Pdx1, which controls the expression of numerous genes involved in maintaining β-cell function and identity. Pdx1 activity is modulated by transcriptional coregulators and has recently been shown, through an unbiased screen, to interact with the Chd4 ATPase subunit of the nucleosome remodeling and deacetylase complex. Chd4 contributes to the maintenance of cellular identity and functional status of numerous different cell types. Here, we demonstrated that Pdx1 dynamically interacts with Chd4 under physiological and stimulatory conditions within islet β-cells and established a fundamental role for Chd4 in regulating insulin secretion and modulating numerous Pdx1-bound genes in vitro, including the MafA TF, where we discovered Chd4 is bound to the MafA region 3 enhancer. Furthermore, we found that Pdx1:Chd4 interactions are significantly compromised in islet β-cells under metabolically induced stress in vivo and in human donor tissues with T2D. Our findings establish a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes in vitro, and disruption of Pdx1:Chd4 interactions coincides with β-cell dysfunction associated with T2D.

 

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