Abstract
The orphan nuclear receptor estrogen-related receptor-γ (ERRγ) is a constitutively active transcription factor regulating genes involved in several important cellular processes, including hepatic glucose metabolism, alcohol metabolism, and the endoplasmic reticulum (ER) stress response. cAMP responsive element-binding protein H (CREBH) is an ER-bound bZIP family transcription factor that is activated upon ER stress and regulates genes encoding acute-phase proteins whose expression is increased in response to inflammation. Here, we report that ERRγ directly regulates CREBH gene expression in response to ER stress. ERRγ bound to the ERRγ response element (ERRE) in the CREBH promoter. Overexpression of ERRγ by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERRγ or inhibition of ERRγ by ERRγ specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1α was required for ERRc mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERRγ and PGC1α on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERRγ and PGC1α binding site. Moreover, chronic alcoholic hepatosteatosis, as well as the diabetic obese condition significantly increased CRP gene expression, and this increase was significantly attenuated by GSK5182 treatment. We suggest that orphan nuclear receptor ERRc directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions.
| Original language | English |
|---|---|
| Article number | e86342 |
| Journal | PLoS One |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2014 Jan 22 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Orphan nuclear receptor errγ induces C-reactive protein gene expression through induction of ER-bound bzip transmembrane transcription factor CREBH. / Misra, Jagannath; Chanda, Dipanjan; Kim, Don Kyu; Cho, Seung Rye; Koo, Seung-Hoi; Lee, Chul Ho; Back, Sung Hoon; Choi, Hueng Sik.
In: PLoS One, Vol. 9, No. 1, e86342, 22.01.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Orphan nuclear receptor errγ induces C-reactive protein gene expression through induction of ER-bound bzip transmembrane transcription factor CREBH
AU - Misra, Jagannath
AU - Chanda, Dipanjan
AU - Kim, Don Kyu
AU - Cho, Seung Rye
AU - Koo, Seung-Hoi
AU - Lee, Chul Ho
AU - Back, Sung Hoon
AU - Choi, Hueng Sik
PY - 2014/1/22
Y1 - 2014/1/22
N2 - The orphan nuclear receptor estrogen-related receptor-γ (ERRγ) is a constitutively active transcription factor regulating genes involved in several important cellular processes, including hepatic glucose metabolism, alcohol metabolism, and the endoplasmic reticulum (ER) stress response. cAMP responsive element-binding protein H (CREBH) is an ER-bound bZIP family transcription factor that is activated upon ER stress and regulates genes encoding acute-phase proteins whose expression is increased in response to inflammation. Here, we report that ERRγ directly regulates CREBH gene expression in response to ER stress. ERRγ bound to the ERRγ response element (ERRE) in the CREBH promoter. Overexpression of ERRγ by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERRγ or inhibition of ERRγ by ERRγ specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1α was required for ERRc mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERRγ and PGC1α on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERRγ and PGC1α binding site. Moreover, chronic alcoholic hepatosteatosis, as well as the diabetic obese condition significantly increased CRP gene expression, and this increase was significantly attenuated by GSK5182 treatment. We suggest that orphan nuclear receptor ERRc directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions.
AB - The orphan nuclear receptor estrogen-related receptor-γ (ERRγ) is a constitutively active transcription factor regulating genes involved in several important cellular processes, including hepatic glucose metabolism, alcohol metabolism, and the endoplasmic reticulum (ER) stress response. cAMP responsive element-binding protein H (CREBH) is an ER-bound bZIP family transcription factor that is activated upon ER stress and regulates genes encoding acute-phase proteins whose expression is increased in response to inflammation. Here, we report that ERRγ directly regulates CREBH gene expression in response to ER stress. ERRγ bound to the ERRγ response element (ERRE) in the CREBH promoter. Overexpression of ERRγ by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERRγ or inhibition of ERRγ by ERRγ specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1α was required for ERRc mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERRγ and PGC1α on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERRγ and PGC1α binding site. Moreover, chronic alcoholic hepatosteatosis, as well as the diabetic obese condition significantly increased CRP gene expression, and this increase was significantly attenuated by GSK5182 treatment. We suggest that orphan nuclear receptor ERRc directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions.
UR - http://www.scopus.com/inward/record.url?scp=84899672824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899672824&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0086342
DO - 10.1371/journal.pone.0086342
M3 - Article
C2 - 24466039
AN - SCOPUS:84899672824
VL - 9
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 1
M1 - e86342
ER -