The Glucocorticoid Receptor Regulates the ANGPTL4 Gene in a CTCF-Mediated Chromatin Context in Human Hepatic Cells.

Masafumi Nakamoto,Akiyuki Hirosue,Masanori Shinohara,Mitsuyoshi Nakao,Shinjiro Hino,Ko Ishihara,Hideki Nakayama,Takehisa Watanabe,Hodaka Fujii

doi:10.1371/journal.pone.0169225

Masafumi Nakamoto, Akiyuki Hirosue + Show 7 more

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https://doi.org/10.1371/journal.pone.0169225

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Abstract

Glucocorticoid signaling through the glucocorticoid receptor (GR) plays essential roles in the response to stress and in energy metabolism. This hormonal action is integrated to the transcriptional control of GR-target genes in a cell type-specific and condition-dependent manner. In the present study, we found that the GR regulates the angiopoietin-like 4 gene (ANGPTL4) in a CCCTC-binding factor (CTCF)-mediated chromatin context in the human hepatic HepG2 cells. There are at least four CTCF-enriched sites and two GR-binding sites within the ANGPTL4 locus. Among them, the major CTCF-enriched site is positioned near the ANGPTL4 enhancer that binds GR. We showed that CTCF is required for induction and subsequent silencing of ANGPTL4 expression in response to dexamethasone (Dex) and that transcription is diminished after long-term treatment with Dex. Although the ANGPTL4 locus maintains a stable higher-order chromatin conformation in the presence and absence of Dex, the Dex-bound GR activated transcription of ANGPTL4 but not that of the neighboring three genes through interactions among the ANGPTL4 enhancer, promoter, and CTCF sites. These results reveal that liganded GR spatiotemporally controls ANGPTL4 transcription in a chromosomal context.

Highlights

The glucocorticoid receptor (GR) is a member of a family of transcription factors that regulate biological processes, such as basal and stress-associated homeostasis, energy metabolism, and the immune response in a cell-type and condition-dependent manner [1, 2]
The decrease in the level of angiopoietin-like 4 gene (ANGPTL4) mRNA coexisted with a high level of GR binding to the AG sites 24 h after Dex addition (Figs 1B and 2A). These results suggest that Dex-induced ANGPTL4 expression was regulated by the CCCTC-binding factor (CTCF)-mediated chromatin context as well as by GR binding to the enhancers
Our results suggest that 1) the ANGPTL4 locus maintains the stable higher-order chromatin conformation under basal conditions and Dex treatment and 2) ANGPTL4 is selectively activated by liganded GR via the associations among the enhancer, promoter, and CTCF sites

Summary

Introduction

The glucocorticoid receptor (GR) is a member of a family of transcription factors that regulate biological processes, such as basal and stress-associated homeostasis, energy metabolism, and the immune response in a cell-type and condition-dependent manner [1, 2]. In the absence of ligand, GR is present in the cytoplasm in a complex with chaperons such as heat-shock proteins. Upon ligand-induced activation, GR dissociates from the complex and translocates to the nucleus, typically by binding to the glucocorticoid response elements (GREs) to activate or repress transcription of target genes. GR dissociates from its ligand or is degraded [2].

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