The Transcriptional Co-Regulator HCF-1 Is Required for INS-1 β-cell Glucose-Stimulated Insulin Secretion

Terri N Iwata,Timothy J Cowley,Yewei Ji,Michael Sloma,Hana Kim,Siu Sylvia Lee,Ling Qi,Juergen Eckel

doi:10.1371/journal.pone.0078841

Abstract

The transcriptional co-regulator host cell factor-1 (HCF-1) plays critical roles in promoting cell cycle progression in diverse cell types, and in maintaining self-renewal of embryonic stem cells, but its role in pancreatic β-cell function has not been investigated. Immunhistochemistry of mouse pancreas revealed nuclear expression of HCF-1 in pancreatic islets. Reducing HCF-1 expression in the INS-1 pancreatic β-cell line resulted in reduced cell proliferation, reduced glucose-stimulated insulin secretion, and reduced expression of the critical β-cell transcription factor Pdx1. HCF-1 is a known co-activator of the E2F1 transcription factor, and loss of E2F1 results in pancreatic β-cell dysfunction and reduced expression of Pdx1. Therefore we wondered whether HCF-1 might be required for E2F1 regulation of Pdx1. Chromatin immunoprecipitation experiments revealed that HCF-1 and E2F1 co-localize to the Pdx1 promoter. These results indicate that HCF-1 represents a novel transcriptional regulator required for maintaining pancreatic β-cell function.

Highlights

Diabetes develops due to a deficiency in circulating insulin caused by pancreatic b-cell destruction and/or impaired b-cell function
While a number of key DNA-binding transcription factors are known to be critical in regulating the proliferation, survival, differentiation, and proper functioning of b-cells [3,4], relatively little is known about the transcriptional co-factors that act to assemble appropriate transcriptional complexes and enable transcription factors to carry out their functions
The transcriptional co-regulator host cell factor-1 (HCF-1) is emerging as a critical co-factor to many different DNA-binding transcription factors with key roles ranging from cell cycle progression [5,6] and DNA-damage induced apoptosis [7] to maintenance of embryonic stem cell pluripotency [8]

Summary

Introduction

Diabetes develops due to a deficiency in circulating insulin caused by pancreatic b-cell destruction and/or impaired b-cell function. We demonstrate an essential role for HCF-1 in glucose-stimulated insulin secretion in the INS-1 pancreatic b-cell line suggesting that HCF-1 represents a promising future therapeutic target for the prevention and treatment of diabetes. Consistent with previous studies showing the importance of HCF-1 in regulating cell cycle progression in various cell lines [5,6,12], INS-1 b-cells treated with three different HCF-1 targeting siRNAs exhibited defects in cell growth over time as well as decreased BrdU incorporation (Figure S1A and S1C) indicating a defect in cell proliferation.

Results

Conclusion