RORA

The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The specific functions of this protein are not known, but it has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq]

RORA

Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development (PubMed:29656859).
Regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC1 and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. 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, 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. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.

Biological Process angiogenesisManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process cellular response to hypoxiaManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process cellular response to interleukin-1IEA:Ensembl
Biological Process cellular response to sterolManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process cellular response to tumor necrosis factorIEA:Ensembl
Biological Process cerebellar granule cell precursor proliferationISS:UniProtKB
Biological Process cerebellar Purkinje cell differentiationIEA:Ensembl
Biological Process cGMP metabolic processIEA:Ensembl
Biological Process cholesterol homeostasisISS:UniProtKB
Biological Process circadian regulation of gene expressionISS:UniProtKB
Biological Process intracellular receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process muscle cell differentiationManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process negative regulation of fat cell differentiationISS:UniProtKB
Biological Process negative regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process negative regulation of inflammatory responseManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process nitric oxide biosynthetic processIEA:Ensembl
Biological Process positive regulation of circadian rhythmISS:UniProtKB
Biological Process positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:MGI
Biological Process positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of vascular endothelial growth factor productionManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process regulation of glucose metabolic processISS:UniProtKB
Biological Process regulation of macrophage activationIEA:Ensembl
Biological Process regulation of smoothened signaling pathwayISS:UniProtKB
Biological Process regulation of steroid metabolic processISS:UniProtKB
Biological Process regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
Biological Process regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process T-helper 17 cell differentiationIEA:Ensembl
Biological Process triglyceride homeostasisManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process xenobiotic metabolic processISS:UniProtKB

Nucleus

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA):
An autosomal dominant neurodevelopmental disorder that manifests with variable features of mild-to-severe intellectual disability, developmental delay, autism spectrum disorder, cerebellar ataxia and epilepsy.

Phosphorylation by conventional PKCs in neurons inhibits transcriptional activity. Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro.
Sumoylated by SENP1 and SENP2. Sumoylation, promoted by PIAS2, PIAS3, PIAS4 but not PIAS1, enhances the transcriptional activity. Desumoylated by SENP1.
Ubiquitinated, leading to its degradation by the proteasome. Proteasomal degradation is required for efficient transcriptional activity and is prevented by HR.
Isoform 1
Monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.