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 cellular differentiation, immunity, peripheral 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 gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. 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 RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA 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 SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC1 and PCK1. Regulates the rhythmic expression of PROX1 and promotes its nuclear localization. Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity.; Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches. Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for 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. May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus.

1. Herein, molecular dynamics simulations were conducted on HC9-ROR-gamma and XY018-ROR-gamma complexes to understand their conformational features at molecular level and the influence of XY018 binding on the dynamics of ROR-gamma with the aid of post-dynamic analytical tools. PMID: 28027708
2. RORgammat mRNA expression levels were significantly different among groups of Hepatitis B virus infection patients with different disease severities. PMID: 30045265
3. siRNA-mediated knockdown of T-bet and RORgammaT contributes to decreased inflammation in preeclampsia. PMID: 28849203
4. There was no significant difference in FOXP3, RORgammat, IL-10 protein expression and supernatant PBMCs IL-10 in chronic heart failure patients as compared to control. PMID: 29198133
5. TNF-alpha inhibitors decrease histone (H)3 and H4 acetylation in the RORgammat gene promotor region by decreasing the recruitment of the acetyltransferases p300, CBP and PCAF in Th17 cells, from rheumatoid arthritis patients. PMID: 27926504
6. Here we attempt a comprehensive review of the post-translational regulation of RORgammat, an area that holds the potential to transform the way we target the RORgammat/IL-17 pathway PMID: 27481185
7. RORgamma mediates epithelial-mesenchymal transition of hepatocytes during hepatic fibrosis facilitated by TGFbeta1. PMID: 27791279
8. The interaction between c-Maf and RORgammat, and Blimp-1. PMID: 28300844
9. this review on RORC as a transcription factor required for the generation of type 3 lymphoid cells, which induce the development of lymphoid tissues, provide resistance of epithelial stem cells to injury, maintain homeostasis with the symbiotic microbiota, orchestrate defense against extracellular microbes, and regulate allergic responses PMID: 27706126
10. IKKalpha-dependent phosphorylation of S376 stimulated whereas IKKalpha-independent phosphorylation of S484 inhibited RORgammat function in Th17 differentiation. PMID: 28667162
11. There are 2 putative binding motifs for specificity protein transcription factors from the specificity protein/Kruppel-like factor family in the promoter of human RORgammaT. SP2 recognized binding motifs in the human RORgammaT promoter, which was critical for maintaining expression. PMID: 27256574
12. this study shows that all human innate lymphoid cells can be generated through an RORgammat+ developmental pathway from a common progenitor in secondary lymphoid tissues PMID: 27178467
13. ROR-gamma is overexpressed and amplified in metastatic castration resistant prostate tumors, and ROR-gamma drives androgen receptor (AR) expression in the tumors. ROR-gamma recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. PMID: 27019329
14. Data suggest that apo RORC adopts active conformation capable of recruiting coactivator peptides that stabilize helix 12 of the active state in the absence of a ligand; ligand-bound RORC binds inverse agonists that disrupt critical interactions that stabilize helix 12; helix 12 destabilization in the active state shifts the conformational equilibrium of RORC toward an inactive state. PMID: 28546429
15. There is selective migration or survival of RORgammat-positive cells in Secondary Progressive Multiple Sclerosis patient meninges. PMID: 27413074
16. Retinoid-related orphan receptor gammat may be associated with NK22 cells in reproduction. Particularly, higher expression of retinoid-related orphan receptor gammat may be associated with elevated NK22 cells in unexplained recurrent pregnancy loss. PMID: 27374797
17. Study reports on the role of RORgamma in the regulation of genetic programs and pathways promoting breast carcinogenesis. It shows that RORgamma expression is associated with checkpoint control and DNA-repair genes and, its up-regulation is associated with the higher probability of metastasis-free survival. PMID: 27211549
18. Results from the study establish RORgamma as a key player in castration-resistant prostate cancer (CRPCa) by acting upstream of AR and as a new therapeutic target for advanced PCa. PMID: 27019329
19. MiR-16 may be involved in Th17/Treg imbalance in rheumatoid arthritis patients by affecting the expression of RORgt and FoxP3. PMID: 27875659
20. Serum RORC levels was higher in rheumatoid arthritis (RA) patients with rs9826AA, rs12045886TT and -TC, and rs9017AA genotypes compared to healthy subjects with the same genotypes (p = 0.02, p = 0.04 and p = 0.01, respectively). PMID: 27043554
21. The findings suggest that RORC plays a significant role in the dysregulated immune response associated with lupus erythematosus (SLE) . PMID: 26498317
22. High RORgammaT expression is associated with lymph node metastasis in Colorectal Cancer. PMID: 26564244
23. RORgammat is acetylated, and this acetylation is reciprocally regulated by the histone acetyltransferase p300 and the histone deacetylase HDAC1. PMID: 26549310
24. A high copy number of T-bet and GATA-3 confers susceptibility to AAU and AS, and a high copy number of FOXP3 confers susceptibility to female patients with AAU either with or without AS. PMID: 27082299
25. melatonin suppresses HIF-1alpha accumulation and VEGF generation via inhibition of melatonin nuclear receptor RZR/RORgamma in SGC-7901 cells under hypoxia. PMID: 26330273
26. Results reveal differential requirements for ROR-gammat in the maintenance of TH17 cell and group 3 innate lymphoid cell responses in intestinal inflammation. PMID: 26878233
27. The mRNA expression of RORC, TNF-alpha and IL-6 was significantly high in CC patients PMID: 26474968
28. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORgammat ligand binding domain. PMID: 26640126
29. High RORC2 expression is associated with non-small cell lung cancer. PMID: 26319393
30. the balance between the transcription factors of Treg and Th17 cells (FoXp3 and RORgammat) was sought as a molecular marker of disease activity and to highlight the pathogenesis of autoimmune liver diseases PMID: 26434354
31. The QSAR models and the results of molecular docking, MD simulation, binding free energies corroborate well with each other and further provide insights regarding the development of novel RORgt inhibitors with better activity PMID: 25341687
32. findings reveal a direct link between TRAF5-mediated ubiquitination and RORgammat protein regulation PMID: 26453305
33. Our study showed that high CNVs of Rorc and low CNVs of Foxp3 confer risk for BD but not for VKH syndrome. PMID: 25873156
34. Data show that the expression levels of transcription factors GATA-3 and FOXP3 were upregulated with 1.0 mug/ml galectin-1, while transcription factors TBX21 and RORC expression levels were reduced with both 1.0 and 2.0 mug/ml concentrations of galectin-1. PMID: 25292313
35. Data show that co-culturing with exopolysaccharides from Cyanobacterium aponinum (EPS-Ca) treated dendritic cells (DCs) reduced the IL-17+RORgammat+/IL-10+FoxP3+ ratio in CD4+ T cells. PMID: 25499021
36. Data show that the number of retinoic-acid-related orphan receptor (RORC1/RORgamma) monocytic and granulocytic myeloid-derived suppressor cells (M-MDSCs) and polymorphonuclear-myeloid-derived suppressor cells increased in colorectal cancer patients. PMID: 26267538
37. The mRNA levels of RORC in peripheral blood lymphocytes of hepatocellular carcinoma patients were significantly increased, indicating the existence of a predominant phenomenon of Treg-expressing peripheral blood lymphocytes in hepatocellular carcinoma. PMID: 25552913
38. RORgammat mRNA increased with tumor size and multiple tumor foci in hepatocellular carcinoma PMID: 26415373
39. Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorgammaT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung PMID: 25491772
40. this study reports the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. PMID: 26160376
41. USP4 and IL-17 mRNA, but not RORgammat mRNA, were significantly elevated in CD4(+) T cells from patients with rheumatic heart disease PMID: 25821221
42. Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclassic Th1 cells. PMID: 25740946
43. These results demonstrate that estradiol upregulates REA expression and recruits REA via ERalpha to the EREs on the RORgammaT promoter region, thus inhibiting RORgammaT expression and Th17 differentiation. PMID: 25769926
44. Expression of mRNA of transcription factors RORC2 and FoxP3 in lymphocytes in patients with pulmonary tuberculosis reflects the stages of disease progression and prognosis. PMID: 25872376
45. RORgammat-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. PMID: 25527718
46. This study demonstrates the role and significant correlation between a histone methyltransferase (PRMT2)-dependent signature, RORgamma, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes. PMID: 24911119
47. Our data reveal a molecular mechanism in which RORgammat expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions. PMID: 25070893
48. Expression of RORC in nasal epithelial cells was higher in nasal polyps compared to control mucosa. PMID: 23765061
49. Neutrophils, but not mast cells, coexpressed the IL-17-associated transcription factor RORgammat and were able to form extracellular traps. PMID: 24317395
50. Data suggest that RORgammat is a tractable drug target for the treatment of cutaneous inflammatory disorders. PMID: 24516202

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Nucleus.

Nuclear hormone receptor family, NR1 subfamily

Isoform 1 is widely expressed in many tissues, including liver and adipose, and highly expressed in skeletal muscle. Isoform 2 is primarily expressed in immature thymocytes.

HGNC: 10260

OMIM: 602943

KEGG: hsa:6097

STRING: 9606.ENSP00000327025

UniGene: Hs.256022