NPAS2
Description
The NPAS2 (neuronal PAS domain protein 2) is a protein-coding gene located on chromosome 2.
Neuronal PAS domain protein 2 (NPAS2), also known as member of PAS protein 4 (MOP4), is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.
== Discovery == The mammalian and mouse Npas2 gene was first sequenced and characterized in 1997 Dr. Steven McKnight's lab and published by Yu-Dong Zhou et al. The gene’s cDNAs encoding mouse and human forms of NPAS2 were isolated and sequenced. RNA blotting assays were used to demonstrate the selective presence of the gene in brain and spinal cord tissues of mice. In situ hybridization indicated that the pattern of Npas2 mRNA distribution in mouse brain is broad and complex, and is largely non-overlapping with that of Npas1. Using Immunohistochemistry of human testis, Ramasamy et al.
NPAS2 is a transcriptional activator that plays a critical role in the circadian clock, an internal timekeeping system that regulates various physiological processes by generating approximately 24-hour rhythms in gene expression, influencing metabolism and behavior. It acts as a key regulator of various functions, including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. The circadian clock consists of two main components: the central clock, located in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks present in nearly every tissue and organ system. Both central and peripheral clocks can be reset by environmental cues, known as Zeitgebers. The dominant Zeitgeber for the central clock is light, detected by the retina and transmitted directly to the SCN. The central clock synchronizes peripheral clocks through neuronal and hormonal signals, body temperature, and feeding-related cues, aligning all clocks with the external light-dark cycle. Circadian rhythms enable an organism to achieve temporal homeostasis with its environment by regulating gene expression to create a peak of protein expression once every 24 hours, controlling when a specific physiological process is most active relative to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1, and CRY2) are crucial for rhythm generation, while delays caused by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms. A diurnal rhythm is synchronized with the day-night cycle, while ultradian and infradian rhythms have periods shorter and longer than 24 hours, respectively. Disruptions in circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes, and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, acting as a heterodimer to activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes) harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes, PER1/2/3 and CRY1/2, which are transcriptional repressors, form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer, inhibiting its activity and negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, forming a second feedback loop that activates and represses BMAL1 transcription, respectively. The NPAS2-BMAL1 heterodimer positively regulates the expression of MAOA, F7, and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. NPAS2 plays a vital role in sleep homeostasis and maintaining circadian behaviors in normal light-dark and feeding conditions, as well as in the effective synchronization of feeding behavior with scheduled food availability. It regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes. It controls the circadian rhythm of NR0B2 expression by binding rhythmically to its promoter. It mediates the diurnal variation in the expression of GABARA1 receptor in the brain and contributes to the regulation of anxiety-like behaviors and GABAergic neurotransmission in the ventral striatum. NPAS2 is a component of the circadian clock oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Efficient DNA binding requires dimerization with another bHLH protein. NPAS2 forms a heterodimer with BMAL1, and this heterodimerization is required for E-box-dependent transactivation. It interacts with NCOA3, KAT2B, CREBBP, and EP300.
NPAS2 is also known as MOP4, PASD4, bHLHe9.
