Emerging Insight Into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence

Abstract

Cell senescence is a crucial process in cell fate determination and is involved in an extensive array of aging-associated diseases. General perceptions and experimental evidence point out that the decline of physical function as well as aging-associated diseases are often initiated by cell senescence and organ ageing. Therefore, regulation of cell senescence process can be a promising way to handle aging-associated diseases such as osteoporosis. The circadian clock regulates a wide range of cellular and physiological activities, and many age-linked degenerative disorders are associated with the dysregulation of clock genes. BMAL1 is a core circadian transcription factor and governs downstream genes by binding to the E-box elements in their promoters. Compelling evidence has proposed the role of BMAL1 in cellular senescence and aging-associated diseases. In this review, we summarize the linkage between BMAL1 and factors of cell senescence including oxidative stress, metabolism, and the genotoxic stress response. Dysregulated and dampened BMAL1 may serve as a potential therapeutic target against aging- associated diseases.

Keywords: BMAL1; aging; cellular senescence; genotoxic stress; metabolism; oxidative stress.

Figure 1

Role of BMAL1 in the circadian rhythm. The circadian rhythm involves a negative-feedback loop and an accessory feedback loop. In the negative-feedback loop, the CLOCK and BMAL1 form a heterodimer that activates the PER and CRY genes by directly interacting with the E-Box element. Subsequently, accumulation of PER/CRY protein complexes inhibits the expression of BMAL1/CLOCK. In the accessory feedback loop, the transcription of BMAL1/CLOCK is controlled by positive regulators (RORα, RORβ and RORγ) and negative regulators (REV-ERBα and REV-ERBβ). ClOCK and BMAl1, in turn, regulate the expression of RORs and REV-ERBs.

Figure 2

(A) The role of BMAL1 in the Nrf2 pathway. CLOCK/BMAL1 complexes exert temporal control on the E-box element in the Nrf2 gene promoter and positively regulate Nrf2 transcription. Nrf2 protein accumulates in a circadian manner and drives oscillations of ARE-regulated antioxidant genes. On the other hand, Nrf2 regulates the expression of PER, CRY, REV-ERBα/β, which represses CLOCK/BMAL1-regulated E-box transcription and switches off their production. (B) The role of BMAL1 in the NFκB pathway. On one hand, NFκB activation is under the regulation of a loop represented by the clock genes BMAL1/CLOCK, and their transcriptional positive and negative regulators REV-ERBα and RORα. Activation of this pathway leads to enhanced NAD+ levels and SIRT1 deacetylase activity, which in turn inactivates NFκB and reduces the binding ability to DNA. CLOCK upregulates NFκB–mediated transcription by increasing p65 phosphorylation and acetylation in the absence of BMAL1, and BMAL1 downregulates the CLOCK-dependent modulation of NFκB activation. On the other hand, NFκB antagonizes transcription of the CLOCK/BMAL1 target genes by directly binding to the promoters of the core clock repressors PER and CRY, which leads to highly specific transcriptional repression of CLOCK/BMAL1.

Figure 3

(A) The role of BMAL1 in glucose metabolism. BMAL1 controls hepatic glucose metabolism and pancreatic β-cell insulin secretion. In skeletal muscle, muscle-specific loss of BMAL1 results in reduced glucose oxidation. In addition to the hormone regulation of global glucose homeostasis, BMAL1 participates in concrete glucose metabolism processes. BMAL1 restrains glycolysis levels, while activation of BMAL1 inhibits pyruvate dehydrogenase kinase (PDK), resulting in the disinhibition of the pyruvate dehydrogenase complex (PDC). Then PDC drives the conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA) in mitochondria, thus increasing the TCA cycle, OXPHOS and ATP production. Loss-of function of BMAL1 leads to the disruption of the aforementioned process and cellular senescence. (B) The role of BMAL1 in lipid metabolism. In the liver, BMAL1 regulates lipid synthesis, fatty acid oxidation, lipolysis and lipid homeostasis. Hepatocyte BMAL1 is required for post-prandial de novo lipogenesis through insulin-mTORC2-AKT- ChREBP-lipogenesis. BMAL1 regulates fatty acid oxidation by activating the transcription of the PPARα gene by binding to the E-box within the gene promoter. BMAL1 also regulates homeostasis lipogenesis through CREBH. In white adipose tissue, BMAL1 regulates genes involved in lipogenesis such as SREBP-1a and REV-ERB α, resulting in the promotion of lipid synthesis and accumulation. BMAL1 regulates lipid storage through the expression of Adipoq, Retn, Nampt, AdipoR1 and AdipoR2. BMAL1 regulates lipolysis by directly and rhythmically binding to Eboxes in the promoters of Atgl and Hsl. In skeletal muscle, BMAL1 regulates oxidative capacity and fat oxidation activity through the regulation of Cacnas expression, followed by the NFAT axis. (C) The role of BMAL1 in amino acid metabolism. In muscle tissue, loss of function of BMAL1 is associated with protein catabolism. increased glucogenic amino acids (alanine, glutamine, glutamate, glycine, serine, threonine, methionine, proline, and aspartate) as well as BCAAs (leucine, isoleucine, and valine). In the liver, loss of BMAL1 leads to an increase in blood plasma amino acids, such as glutamine, glutamate, glycine, serine, proline, leucine, and valine. In SCN, loss of BMAL1 increases most neurotransmitter amino acid, such as excitatory (Aspartate, Glutamate) or inhibitory (Glycine) and precursors (Glutamine).

Figure 4

The role of BMAL1 in the genotoxic stress response. The effect of BMAL1 in the genotoxic stress response involves regulation of the DDR pathway and cell cycle (G1/S transition and G2/M transition). BMAL1 regulates the key DSB detection and signaling gene ATM by directly binding to the ATM promoter region. At the bottom of the DDR cascade, BMAL1 regulates p53 by binding to the p53 gene promoter region and transcriptionally activating p53 phosphorylation. BMAL1 regulates some key molecules in the G1/S transition such as p21, Cdk4/6, and Cyclin D. BMAL1 regulates some key molecules in the G2/M transition such as Wee1, cdc2 and Cylin B.