Expression of BMAL (ARNTL), CLOCK, and NPAS2

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R-HSA-9931509
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Pathway
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Homo sapiens
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5/5
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Expression of BMAL (ARNTL), CLOCK, and NPAS2
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BMAL1 (ARNTL), CLOCK, and NPAS2, which acts redundantly with CLOCK, are key activators of diurnal circadian gene expression (reviewed in Cox and Takahashi 2019). Their expression is positively regulated by the Retinoid-related orphan receptors RORA, RORB, and RORC and negatively regulated by the nuclear receptor NR1D1 (REV-ERBA), all of which complete for the same ROR responsive elements (RRE, RORE) (inferred from mouse homologs in Ueda et al. 2002, Guilaumond et al. 2005) in the BMAL1 promoter (inferred from the mouse homolog in Sato et al. 2004, Akashi and Takumi 2005, Guillaumond et al. 2005, Takeda et al. 2012) and CLOCK promoter (inferred from mouse homologs in Lau et al. 2004, Takeda et al. 2012). ROR nuclear receptors bind oxysterols (Wang et al. 2010) while NR1D1 binds heme (Yin et al. 2007, Raghuram et al. 2007), thus providing potential links with metabolism.
ROR nuclear receptors recruit coactivators of transcription such as EP300 (p300), PPARGC1A (PGC1A) (inferred from mouse homologs in Lau et al. 2004), and NRIP1 (Poliandri et al. 2011) to activate transcription by RNA polymerase II. In contrast, heme-bound NR1D1 recruits the corepressor NCOR1, and the histone deacetylase HDAC3 to repress transcription (Wu et al. 2009).
The genes encoding RORA, RORC, and NR1D1 regulate BMAL1 and CLOCK and are regulated by BMAL1 and CLOCK, thereby constituting a secondary loop in the mammalian circadian clock.
Literature References
PubMed ID Title Journal Year
12152080 A transcription factor response element for gene expression during circadian night

Ueda, HR, Chen, W, Adachi, A, Wakamatsu, H, Hayashi, S, Takasugi, T, Nagano, M, Nakahama, K, Suzuki, Y, Sugano, S, Iino, M, Shigeyoshi, Y, Hashimoto, S

Nature 2002
31557726 Circadian clock genes and the transcriptional architecture of the clock mechanism

Cox, KH, Takahashi, JS

J Mol Endocrinol 2019
19965867 Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands

Wang, Y, Kumar, N, Solt, LA, Richardson, TI, Helvering, LM, Crumbley, C, Garcia-Ordonez, RD, Stayrook, KR, Zhang, X, Novick, S, Chalmers, MJ, Griffin, PR, Burris, TP

J Biol Chem 2010
21628546 Modulation of clock gene expression by the transcriptional coregulator receptor interacting protein 140 (RIP140)

Poliandri, AH, Gamsby, JJ, Christian, M, Spinella, MJ, Loros, JJ, Dunlap, JC, Parker, MG

J. Biol. Rhythms 2011
15199055 RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR

Lau, P, Nixon, SJ, Parton, RG, Muscat, GE

J Biol Chem 2004
15312651 A functional genomics strategy reveals Rora as a component of the mammalian circadian clock

Sato, TK, Panda, S, Miraglia, LJ, Reyes, TM, Rudic, RD, McNamara, P, Naik, KA, FitzGerald, GA, Kay, SA, Hogenesch, JB

Neuron 2004
15821743 The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1

Akashi, M, Takumi, T

Nat Struct Mol Biol 2005
16267379 Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors

Guillaumond, F, Dardente, H, Giguère, V, Cermakian, N

J Biol Rhythms 2005
18006707 Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways

Yin, L, Wu, N, Curtin, JC, Qatanani, M, Szwergold, NR, Reid, RA, Waitt, GM, Parks, DJ, Pearce, KH, Wisely, GB, Lazar, MA

Science 2007
18037887 Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta

Raghuram, S, Stayrook, KR, Huang, P, Rogers, PM, Nosie, AK, McClure, DB, Burris, LL, Khorasanizadeh, S, Burris, TP, Rastinejad, F

Nat Struct Mol Biol 2007
22753030 RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo

Takeda, Y, Jothi, R, Birault, V, Jetten, AM

Nucleic Acids Res 2012
19710360 Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha

Wu, N, Yin, L, Hanniman, EA, Joshi, S, Lazar, MA

Genes Dev 2009
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Authored
May, B  (2024-12-09)
Reviewed
Sancar, A  (2025-02-14)
Albrecht, U  (2025-02-18)
Created
May, B  (2024-12-12)
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