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

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Rebecca K Davidson1,2,3, Staci A Weaver1,2,3, Nolan Casey1,2,3

  • 1Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Journal of Molecular Endocrinology
|May 6, 2022
PubMed

Insights

Type 2 diabetes involves losing key transcription factors (TFs) like Pdx1 in beta cells. This study reveals Chd4 protein is crucial for Pdx1 function and insulin secretion, with interactions disrupted in diabetes.

Area of Science:

  • Molecular biology
  • Endocrinology
  • Diabetes research

Background:

  • Type 2 diabetes (T2D) is linked to the loss of critical transcription factors (TFs) in pancreatic beta cells.
  • Pdx1 is a key TF regulating beta cell function and identity, whose activity is modulated by interacting proteins.
  • Chd4, a component of the nucleosome remodeling and deacetylase complex, maintains cellular identity and function.

Purpose of the Study:

  • To investigate the interaction between Pdx1 and Chd4 in beta cells.
  • To determine the role of Chd4 in regulating insulin secretion and Pdx1-bound genes.
  • To examine the impact of metabolic stress and T2D on Pdx1:Chd4 interactions in vivo and in human tissues.

Main Methods:

  • Demonstrated dynamic interaction between Pdx1 and Chd4 in islet beta cells under various conditions.
  • Assessed Chd4's role in regulating insulin secretion and Pdx1-target genes in vitro, including the MafA TF.
  • Analyzed Pdx1:Chd4 interactions in beta cells from animal models with metabolic stress and from human T2D donor tissues.

Main Results:

  • Established that Chd4 dynamically interacts with Pdx1 in beta cells.
  • Confirmed a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes, including MafA.
  • Observed significantly compromised Pdx1:Chd4 interactions in beta cells under metabolic stress and in human T2D tissues.

Conclusions:

  • Chd4 plays a fundamental role in regulating insulin secretion and Pdx1-mediated gene regulation in beta cells.
  • Disruption of Pdx1:Chd4 interactions is associated with beta cell dysfunction in Type 2 diabetes.
  • Targeting the Pdx1:Chd4 interaction may offer a therapeutic strategy for T2D.
Keywords:
Chd4beta cellcoregulatorinsulin secretiontranscription factortype 2 diabetes

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