Abstract
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.
Highlights
Basal metabolic rate is regulated by thyroid hormone; the mechanism is unknown
Thyroid Hormone-responsive Genes Are Differentially Regulated by NCOR1—Studies have shown that T3 regulates thyrotopin subunit gene expression in the T␣T1.1 thyrotroph cell line
thyroid-stimulating hormone (TSH) is central to regulation of the HPT axis, and both subunit genes that comprise TSH are down-regulated by T3 in vivo [29, 32]
Summary
Basal metabolic rate is regulated by thyroid hormone; the mechanism is unknown. Results: NCOR1 and Rev-Erb␣ enrich at different sites from thyroid hormone receptor on the Tshb promoter. Rev-Erb␣ Regulates Tshb Circadian Rhythm induce the expression of type 2 iodothyronine deiodinase in the hypothalamus, which enzymatically converts the prohormone T4 into its bioactive T3 product, providing an additional mechanism for controlling the HPT axis [21, 22]. Given that this diurnal rhythm of TSH is disrupted in states as diverse as depression, poorly controlled diabetes, and mostly importantly, after pharmacologic T4 replacement to hypothyroid patients, further elucidation of this mechanism is warranted [23, 24]. We hypothesize that circadian regulation of TSH and T3 secretion is maintained by NCOR1 interaction with NR1D1, not THR, and that circadian changes in T3 levels may have a previously unrecognized role in controlling overall metabolism
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