TY - JOUR
T1 - Circadian regulation of Tshb gene expression by Rev-Erbα (NR1D1) and nuclear corepressor 1 (NCOR1)
AU - Aninye, Irene O.
AU - Matsumoto, Shunichi
AU - Sidhaye, Aniket R.
AU - Wondisford, Fredric E.
PY - 2014/6/13
Y1 - 2014/6/13
N2 - Thyroid hormones (TH) are critical for development, growth, and metabolism. Circulating TH levels are tightly regulated by thyroid-stimulating hormone (TSH) secretion within the hypothalamic-pituitary-thyroid axis. Although circadian TSH secretion has been well documented, the mechanism of this observation remains unclear. Recently, the nuclear corepressor, NCOR1, has been postulated to regulate TSH expression, presumably by interacting with thyroid hormone receptors (THRs) bound to TSH subunit genes. We report herein the first in vitro study of NCOR1 regulation of TSH in a physiologically relevant cell system, the TαT1.1 mouse thyrotroph cell line. Knockdown of NCOR1 by shRNA adenovirus increased baseline Tshb mRNA levels compared with scrambled control, but surprisingly had no affect on the T3-mediated repression of this gene. Using ChIP, we show that NCOR1 enriches on the Tshb promoter at sites different from THR previously identified by our group. Furthermore, NCOR1 enrichment on Tshb is unaffected by T3 treatment. Given that NCOR1 does not target THR on Tshb, we hypothesized that NCOR1 targeted Rev-Erbα (NR1D1), an orphan nuclear receptor that is a potent repressor of gene transcription and regulator of metabolism and circadian rhythms. Using a serum shock technique, we synchronized TαT1.1 cells to study circadian gene expression. Post-synchronization, Tshb and Nr1d1 mRNA levels displayed oscillations that inversely correlated with each other. Furthermore, NR1D1 was enriched at the same locus as NCOR1 on Tshb. Therefore, we propose a model for Tshb regulation whereby NR1D1 and NCOR1 interact to regulate circadian expression of Tshb independent of TH negative regulation.
AB - Thyroid hormones (TH) are critical for development, growth, and metabolism. Circulating TH levels are tightly regulated by thyroid-stimulating hormone (TSH) secretion within the hypothalamic-pituitary-thyroid axis. Although circadian TSH secretion has been well documented, the mechanism of this observation remains unclear. Recently, the nuclear corepressor, NCOR1, has been postulated to regulate TSH expression, presumably by interacting with thyroid hormone receptors (THRs) bound to TSH subunit genes. We report herein the first in vitro study of NCOR1 regulation of TSH in a physiologically relevant cell system, the TαT1.1 mouse thyrotroph cell line. Knockdown of NCOR1 by shRNA adenovirus increased baseline Tshb mRNA levels compared with scrambled control, but surprisingly had no affect on the T3-mediated repression of this gene. Using ChIP, we show that NCOR1 enriches on the Tshb promoter at sites different from THR previously identified by our group. Furthermore, NCOR1 enrichment on Tshb is unaffected by T3 treatment. Given that NCOR1 does not target THR on Tshb, we hypothesized that NCOR1 targeted Rev-Erbα (NR1D1), an orphan nuclear receptor that is a potent repressor of gene transcription and regulator of metabolism and circadian rhythms. Using a serum shock technique, we synchronized TαT1.1 cells to study circadian gene expression. Post-synchronization, Tshb and Nr1d1 mRNA levels displayed oscillations that inversely correlated with each other. Furthermore, NR1D1 was enriched at the same locus as NCOR1 on Tshb. Therefore, we propose a model for Tshb regulation whereby NR1D1 and NCOR1 interact to regulate circadian expression of Tshb independent of TH negative regulation.
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U2 - 10.1074/jbc.M114.569723
DO - 10.1074/jbc.M114.569723
M3 - Article
C2 - 24794873
AN - SCOPUS:84902436520
SN - 0021-9258
VL - 289
SP - 17070
EP - 17077
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 24
ER -