RORA
Description
The RORA (RAR related orphan receptor A) is a protein-coding gene located on chromosome 15.
RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.
== Discovery == The first three-human isoforms of RORα were initially cloned and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied. In the early 2000s, various studies demonstrated that RORα displays rhythmic patterns of expression in a circadian cycle in the liver, kidney, retina, and lung. Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian suprachiasmatic nucleus. RORα is necessary for normal circadian rhythms in mice, demonstrating its importance in chronobiology.
== Structure == The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.
RORA is a nuclear receptor that binds to DNA as a monomer at specific sites called ROR response elements (RORE). These elements have a core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. RORA plays a crucial role in regulating various biological processes, including embryonic development, cellular differentiation, immunity, circadian rhythm, and metabolism of lipids, steroids, xenobiotics, and glucose. It possesses intrinsic transcriptional activity and can be modulated by natural ligands like oxysterols, which act as agonists (e.g., 25-hydroxycholesterol) or inverse agonists (e.g., 7-oxygenated sterols), enhancing or repressing its transcriptional activity, respectively. RORA recruits different cofactors to target genes' regulatory regions, depending on the tissue, time, and promoter context, thereby fine-tuning their transcriptional expression. It regulates genes involved in photoreceptor development, including OPN1SW, OPN1SM, and ARR3, and skeletal muscle development with MYOD1. RORA is essential for proper cerebellum development, regulating SHH gene expression and promoting granule cells proliferation. It also plays a key role in calcium-mediated signal transduction. RORA regulates the circadian expression of several clock genes, including CLOCK, BMAL1, NPAS2, and CRY1. It competes with NR1D1 for binding to shared DNA response elements on some clock genes, resulting in either NR1D1-mediated repression or RORA-mediated activation of clock genes expression. This competition influences the period length and stability of the circadian clock. RORA regulates genes involved in lipid metabolism, such as apolipoproteins APOA1, APOA5, APOC3, and PPARG. In the liver, it has specific and redundant functions with RORC, acting as a positive or negative modulator of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids, and xenobiotics, such as CYP7B1 and SULT2A1. It induces rhythmic expression of some of these genes. RORA functionally interacts with NR1H2 and NR1H3 in regulating genes involved in cholesterol metabolism. It also participates in regulating hepatic glucose metabolism through the modulation of G6PC1 and PCK1. In adipose tissue, RORA acts as a negative regulator of adipocyte differentiation, potentially through dual mechanisms. It may suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, RORA is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. It likely regulates IL17 and IL17F expression on T(H) cells by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. RORA is involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. It may inhibit cell growth in response to cellular stress and exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.
RORA is also known as IDDECA, NR1F1, ROR1, ROR2, ROR3, RORa1, RORalpha, RZR-ALPHA, RZRA.
