Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes

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R-HSA-9931510
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Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
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After translocation into the nucleus, the phosphorylated BMAL1:CLOCK heterodimer and, by inference, the BMAL1:NPAS2 heterodimer activate transcription by binding E-box elements (consensus: CANNTG) in the promoters of more than 2000 target genes (inferred from mouse homologs in Hatanaka et al. 2010, Guillaume et al. 2011) and recruiting coactivators such as CREB-binding protein (CREBBP) (inferred from mouse homologs in Garg et al. 2019), the histone methylase KMT2A (MLL1) and, presumably, components of the MLL1 complex (inferred from mouse homologs in Katada and Sassone-Corsi 2010). Transcriptional activation by BMAL1:CLOCK occurs during the day, thus genes regulated by BMAL1:CLOCK are diurnally expressed.
Among the thousands of genes activated by BMAL1:CLOCK are the Cryptochrome genes (CRY1, CRY2) and the Period genes (PER1, PER2, PER3) that encode proteins that repress BMAL1:CLOCK activity, forming the primary loop of the circadian clock (reviewed in Cox and Takahashi 2019). BMAL1:CLOCK also activates the expression of Retinoid-related orphan receptor genes RORA, RORB, and RORC and the heme-binding nuclear receptor gene NR1D1 (REV-ERBA) that bind the same ROR responsive elements (RRE, RORE) in the promoters of the BMAL1, CLOCK, and NPAS2 genes. RORA, RORB, RORC activate expression; NR1D1 represses expression. The reciprocal regulation of BMAL1:CLOCK and RORA, RORB, RORC, NR1D1 forms the secondary loop of the circadian clock.
Literature References
PubMed ID Title Journal Year
31557726 Circadian clock genes and the transcriptional architecture of the clock mechanism

Cox, KH, Takahashi, JS

J Mol Endocrinol 2019
21113167 The histone methyltransferase MLL1 permits the oscillation of circadian gene expression

Katada, S, Sassone-Corsi, P

Nat Struct Mol Biol 2010
31515273 Structural and mechanistic insights into the interaction of the circadian transcription factor BMAL1 with the KIX domain of the CREB-binding protein

Garg, A, Orru, R, Ye, W, Distler, U, Chojnacki, JE, Köhn, M, Tenzer, S, Sönnichsen, C, Wolf, E

J Biol Chem 2019
21364973 Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver

Rey, G, Cesbron, F, Rougemont, J, Reinke, H, Brunner, M, Naef, F

PLoS Biol. 2011
20937769 Genome-wide profiling of the core clock protein BMAL1 targets reveals a strict relationship with metabolism

Hatanaka, F, Matsubara, C, Myung, J, Yoritaka, T, Kamimura, N, Tsutsumi, S, Kanai, A, Suzuki, Y, Sassone-Corsi, P, Aburatani, H, Sugano, S, Takumi, T

Mol Cell Biol 2010
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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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