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

If you need an accessible version of this item, please submit a remediation request.
Date
2022-06-14
Language
American English
Embargo Lift Date
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
Bioscientifica
Abstract

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.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Davidson RK, Weaver SA, Casey N, et al. The Chd4 subunit of the NuRD complex regulates Pdx1-controlled genes involved in β-cell function. J Mol Endocrinol. 2022;69(2):329-341. Published 2022 Jun 14. doi:10.1530/JME-22-0011
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Journal of Molecular Endocrinology
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Author's manuscript
Full Text Available at
This item is under embargo {{howLong}}