REVERBA couples the circadian clock to Leydig cell steroidogenesis.
ChIP
Leydig cell
REVERBA
clock
steroidogenesis
testosterone
Journal
BioFactors (Oxford, England)
ISSN: 1872-8081
Titre abrégé: Biofactors
Pays: Netherlands
ID NLM: 8807441
Informations de publication
Date de publication:
26 Dec 2023
26 Dec 2023
Historique:
received:
07
08
2023
accepted:
22
11
2023
medline:
26
12
2023
pubmed:
26
12
2023
entrez:
26
12
2023
Statut:
aheadofprint
Résumé
The involvement of the molecular clock in regulating cell physiological processes on a specific time scale is a recognized concept, yet its specific impact on optimizing androgen production in Leydig cells has been unclear. This study aimed to confirm the role of the REVERBA (NR1D1) gene in controlling the transcription of key genes related to Leydig cell steroid production. We investigated daily variations by collecting Leydig cells from rats at various times within a 24-h period. Chromatin immunoprecipitation study showed a time-dependent pattern for genes linked to steroid production (Nur77, Star, Cyp11a1, and Cyp17a1), which closely matched the 24-h REVERBA levels in Leydig cells, peaking between zeitgeber time (ZT) 7-11. To understand the physiological significance of REVERBA's interaction with promoters of steroidogenesis-related genes, Leydig cells from rats at two different times (ZT7 and ZT16; chosen based on REVERBA expression levels), were treated with either an agonist (GSK4112) or an antagonist (SR8278). The results revealed that the REVERBA agonist stimulated gene transcription, while the antagonist inhibited it, but only when REVERBA was sufficiently present, indicating a reliance on REVERBA's circadian fluctuation. Moreover, this REVERBA-dependent stimulation had a clear impact on testosterone production in the culture medium, underscoring REVERBA's involvement in the circadian regulation of testosterone. This study indicates that REVERBA, in addition to being a core component of the cellular clock, plays a key role in regulating androgen production in Leydig cells by influencing the transcription of critical steroidogenesis-related genes.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Provincial Secretariat for Higher Education and Scientific Research
ID : APV2708
Organisme : Ministry of Science, Technological Development and Innovation of the Republic of Serbia
ID : 451-03-47/2023-01/200125
Organisme : Ministry of Science, Technological Development and Innovation of the Republic of Serbia
ID : CeRES grant
Informations de copyright
© 2023 International Union of Biochemistry and Molecular Biology.
Références
Baburski AZ, Sokanovic SJ, Janjic MM, Stojkov-Mimic NJ, Bjelic MM, Andric SA, et al. Melatonin replacement restores the circadian behavior in adult rat Leydig cells after pinealectomy. Mol Cell Endocrinol. 2015;413:26-35.
Medar ML, Andric SA, Kostic TS. Stress-induced glucocorticoids alter the Leydig cells' timing and steroidogenesis-related systems. Mol Cell Endocrinol. 2021;538:111469.
Baburski AZ, Sokanovic SJ, Bjelic MM, Radovic SM, Andric SA, Kostic TS. Circadian rhythm of the Leydig cells endocrine function is attenuated during aging. Exp Geront. 2016;73:5-13.
Baburski AZ, Andric SA, Kostic TS. Luteinizing hormone signaling is involved in synchronization of Leydig cell's clock and is crucial for rhythm robustness of testosterone production. Biol Reprod. 2019;100(5):1406-1415.
Xiao Y, Zhao L, Li W, Wang X, Ma T, Yang L, et al. Circadian clock gene BMAL1 controls testosterone production by regulating steroidogenesis-related gene transcription in goat Leydig cells. J Cell Physiol. 2021;236(9):6706-6725.
Alvarez J, Hansen A, Ord T, Bebas P, Chappell PE, Giebultowicz JM, et al. The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice. J Biol Rhythms. 2008;23(1):26-36.
Albrecht U, Eichele G. The mammalian circadian clock. Curr Opin Genet Dev. 2003;13(3):271-277.
Yamaguchi S, Mitsui S, Yan L, Yagita K, Miyake S, Okamura H. Role of DBP in the circadian oscillatory mechanism. Mol Cell Biol. 2000;20(13):4773-4781.
Guillaumond F, Dardente H, Giguère V, Cermakian N. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J Biol Rhythms. 2005;20(5):391-403.
Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017;18(3):164-179.
Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, et al. Regulation of circadian behavior and metabolism by REV-ERB-α and REV-ERB-β. Nature. 2012;485(7396):123-127.
Chen H, Chu G, Zhao L, Yamauchi N, Shigeyoshi Y, Hashimoto S, et al. Rev-erbα regulates circadian rhythms and StAR expression in rat granulosa cells as identified by the agonist GSK4112. Biochem Biophys. 2012;420(2):374-379.
Li C, Zhang L, Ma T, Gao L, Yang L, Wu M, et al. Bisphenol A attenuates testosterone production in Leydig cells via the inhibition of NR1D1 signaling. Chemosphere. 2021;263:128020.
Adlanmerini M, Lazar MA. The REV-ERB nuclear receptors: timekeepers for the core clock period and metabolism. Endocrinology. 2023;164(6):bqad069.
Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331(6022):1315-1319.
Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P, et al. The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism. FASEB J. 2012;26(8):3321-3335.
Zhang Y, Fang B, Damle M, Guan D, Li Z, Kim YH, et al. HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev. 2016;30(14):1636-1644.
Sitaula S, Zhang J, Ruiz F, Burris TP. Rev-erb regulation of cholesterologenesis. Biochem Pharmacol. 2017;131:68-77.
Barratt CL, Björndahl L, De Jonge CJ, Lamb DJ, Osorio Martini F, McLachlan R, et al. The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities. Hum Reprod Update. 2017;23(6):660-680.
Sciarra F, Franceschini E, Campolo F, Gianfrilli D, Pallotti F, Paoli D, et al. Disruption of circadian rhythms: a crucial factor in the etiology of infertility. Int J Mol Sci. 2020;21(11):3943.
Kostic TS, Stojkov NJ, Janjic MM, Andric SA. Structural complexity of the testis and PKG I/StAR interaction regulate the Leydig cell adaptive response to repeated immobilization stress. Int J Androl. 2010;33(5):717-729.
Andric SA, Janjic MM, Stojkov NJ, Kostic TS. Testosterone-induced modulation of nitric oxide-cGMP signaling pathway and androgenesis in the rat Leydig cells. Biol Reprod. 2010;83(3):434-442.
Janjic MM, Stojkov NJ, Andric SA, Kostic TS. Anabolic-androgenic steroids induce apoptosis and NOS2 (nitric-oxide synthase 2) in adult rat Leydig cells following in vivo exposure. Reprod Toxicol. 2012;34(4):686-693.
Kostic TS, Stojkov NJ, Janjic MM, Maric D, Andric SA. The adaptive response of adult rat Leydig cells to repeated immobilization stress: the role of protein kinase A and steroidogenic acute regulatory protein. Stress. 2008;11(5):370-380.
Payne AH, Downing JR, Wong KL. Luteinizing hormone receptors and testosterone synthesis in two distinct populations of Ley dig cells. Endocrinology. 1980;106(5):1424-1429.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101-1108.
Dufau ML. The luteinizing hormone receptor. Annu Rev Physiol. 1998;60(1):461-496.
Haider SG. Cell biology of Leydig cells in the testis. Int Rev Cytol. 2004;233(4):181-241.
Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004;25(6):947-970.
de Mattos K, Viger RS, Tremblay JJ. Transcription factors in the regulation of Leydig cell gene expression and function. Front Endocrinol. 2022;13:881309.
Kocerha J, Prucha MS, Kroll KJ, Steinhilber D, Denslow N. Regulation of steroidogenic acute regulatory protein transcription in largemouth bass by orphan nuclear receptor signaling pathways. Endocrinology. 2010;151(1):341-349.
Preitner N, Damiola F, Luis-Lopez-Molina, Zakany J, Duboule D, Albrecht U, et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell. 2002;110(2):251-260.
Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F, et al. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function. Genes Dev. 2012;26(7):657-667.
Ramakrishnan SN, Lau P, Crowther LM, Cleasby ME, Millard S, Leong GM, et al. Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells. Biochem Biophys. 2009;388(4):654-659.
Pavlovic MV, Marinkovic DZ, Andric SA, Kostic TS. The cost of the circadian desynchrony on the Leydig cell function. Sci Rep. 2022;12(1):15520.