Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of twoRev-Erb proteins in thenuclear receptor (NR) family of intracellulartranscription factors. In humans, REV-ERBɑ is encoded by theNR1D1 gene, which is highlyconserved across animal species.[5]
Rev-Erbɑ was discovered in 1989 by Nobuyuki Miyajima and colleagues, who identified twoerbAhomologs on humanchromosome 17 that were transcribed from opposite DNA strands in the samelocus. One of thegenes encoded a protein that was highly similar to chickenthyroid hormone receptor, and the other, which they termedear-1, would later be described as Rev-Erbɑ.[9] The protein was first referenced by the name Rev-Erbɑ in 1990 byMitchell A. Lazar, Karen E. Jones, and William W. Chin, who isolated Rev-Erbɑcomplementary DNA from a human fetal skeletal musclelibrary. Similar to the gene in rats, they found that human Rev-Erbɑ was transcribed from the strand oppositehuman thyroid hormone receptor alpha (THRA, c-erbAα).[10]
Rev-Erbɑ was first implicated in circadian control in 1998, when Aurelio Balsalobre, Francesca Damiola, and Ueli Schibler demonstrated that expression of Rev-Erbɑ in ratfibroblasts showed daily rhythms.[11] Rev-Erbɑ was first identified as a key player in thetranscription translation feedback loop (TTFL) in 2002, when experiments demonstrated that Rev-Erbɑ acted to repress transcription of theBmal1 gene, and Rev-Erbɑ expression was controlled by other TTFL components. This established Rev-Erbɑ as the link between thepositive andnegative loops of the TTFL.[12]
TheNR1D1 (nuclear receptor subfamily 1 group D member 1) gene, located onchromosome 17, encodes the protein REV-ERBɑ in humans. It is transcribed from the opposite strand of the humanthyroid hormone receptor alpha (THRA, c-erbAα) so thatNR1D1 andTHRA cDNA are complementary on 269 bases.[10] The gene consists of 7,797 bases with 8exons, forming only 1splice variant.[5] The NR1D1 promoter itself contains a REV-ERBresponse element (RevRE), which allows for regulation of gene expression both throughautoregulation and regulation byretinoic acid receptor-related orphan receptor alpha (RORɑ), another nuclear receptor transcription factor.[8]NR1D1 also contains anE-box at itspromoter, which allows for regulation byBMAL1. In humans,NR1D1 (REV-ERBɑ) is highly expressed in the brain and metabolic tissues, including skeletal muscle, adipose tissue, and the liver.[8][6]
The humanNR1D1 gene produces a protein product (REV-ERBα) of 614amino acids.[5] REV-ERBα has 3 major functional domains, including aDNA-binding domain (DBD) and aligand-binding domain (LBD) at the C-terminus, and aN-terminus domain which allows for activity modulation.[16][17] These three domains are a common feature of nuclear receptor proteins.[8]
The Rev-Erb proteins are unique from other nuclear receptors in that they do not have ahelix in the C-terminal that is necessary forcoactivator recruitment and activation by nuclear receptors via their LBD.[18] Instead, Rev-Erbα interacts via its LBD withNuclear Receptor Co-Repressor (NCoR) and another closely related co-repressorSilencing Mediator of Retinoid and Thyroid Receptors (SMRT), although the interaction with NCoR is stronger due to its structural compatibility.[18]Heme, anendogenous ligand of Rev-Erbα, further stabilizes the interaction with NCoR.[18][8] The repression by Rev-Erbα also requires interaction with theclass I histone deactylase 3 (HDAC3) - NCoR complex. Thecatalytic activity of HDAC3 is activated only when it complexes with NCoR or SMRT, so Rev-Erbα must interact with this complex in order for gene repression to occur via histone deacetylation.[6] It is still unknown whether other HDACs play a role in the function of Rev-Erbα.[6] Rev-Erbα recruits the NCoR-HDAC3 complex through binding a specific DNA sequence commonly referred to as RORE due to its interaction with the transcriptional activatorRetinoic Acid Receptor-related Orphan Receptor (ROR). This sequence consists of an "AGGTCA" half-site preceded by an A/T sequence..[18] Rev-Erbα binds in themajor groove of this sequence via its DBD domain, which contains twoC4-type zinc fingers.[18] Rev-Erbα can repress gene activation as amonomer throughcompetitive binding at this RORE site, but two Rev-Erbα molecules are required for interaction with NCoR and active gene repression. This can occur by two Rev-Erbα molecules binding separate ROREs or as a stronger interaction through binding aresponse element that is a direct repeat of the RORE (RevDR2).[18]
Rev-Erbα has been proposed to coordinate circadian metabolic responses.[21] Circadian rhythms are driven by interlockingtranscription/translation feedback regulatory loops (TTFLs) that generate and maintain these daily rhythms, and Rev-Erbα is involved in a secondary TTFL in mammals. The primary TTFL features transcriptional activator proteinsCLOCK andBMAL1 that contribute to the rhythmic expression of genes within this loop, notablyper andcry.[22] The expression of these genes then act through negative feedback to inhibit CLOCK:BMAL1 transcription.[12] The secondary TTFL, featuring Rev-Erbα working in conjunction withRev-Erbβ and the orphan receptorRORα, is thought to strengthen this primary TTFL by further regulating BMAL1.[23] RORα shares the same response elements as Rev-Erbα but exerts opposite effects on gene transcription; BMAL1 expression is repressed by Rev-Erbα and activated by RORα.[24] CLOCK:BMAL1 expression activates the transcription ofNR1D1, encoding the Rev-Erbα protein. Increased Rev-Erbα expression in turn, represses transcription of BMAL1, stabilizing the loop.[25] The oscillating expression of RORα and Rev-Erbα in thesuprachiasmatic nucleus, the principal circadian timekeeper in mammals,[26] leads to the circadian pattern of BMAL1 expression. The occupancy of the BMAL1 promoter by these two receptors is key for proper timing of the core clock machinery in mammals.[21]
Rev-erbα plays a role in the regulation of whole body metabolism through controllinglipid metabolism,bile acid metabolism, andglucose metabolism.[27] Rev-Erbα relays circadian signals into metabolic and inflammatory regulatory responses and vice versa, although the precise mechanisms underlying this relationship are not entirely understood.[21]
Rev-erbα regulates the expression of liverapolipoproteins,sterol regulatory element binding protein, and the fatty acidelongaseelovl3 through its repressional activity[28][29][30] In addition, the silencing of Rev-erbα is associated with the reduction of fatty acid synthase, a key regulator oflipogenesis.[30] Rev-erbα deficient mice exhibitdyslipidemia due to elevated triglyceride levels[31] and Rev-erbα polymorphisms in humans have been associated with obesity.[32] Rev-erbα also regulatesadipogenesis of white and brown adipocytes.[9] Rev-Erbα transcription is induced during the adipogenic process, and over-expression of Rev-erbα enhances adipogenesis. Researchers have proposed that Rev-erbα's role in adipocyte function may affect the timing of processes such as lipid storage and lipolysis, contributing to long term issues with BMI control.[28] Rev-erbα also regulates bile acid metabolism by indirectly down-regulatingCyp7A1, which encodes the first and rate controlling enzyme of the major bile acid biosynthetic pathway.[21]
Rev-erbα plays both indirect and direct roles in glucose metabolism. BMAL1 heavily influences glucose production and glycogen synthesis, thus through the regulation of BMAL1, Rev-erbα indirectly regulates glucose synthesis.[33] More directly, Rev-erbα's expression in the pancreas regulates the function ofα-cells andβ-cells, which produce glucagon and insulin, respectively.[34]
Rev-erbα plays a role inmyogenesis through interaction with the transcription complexNuclear Factor-T.[29] It also represses the expression of genes involved in muscle cell differentiation and is expressed in a circadian manner in mouse skeletal muscle. Loss of Rev-erbα function reduces mitochondrial content and function, leading to an impaired exercise capacity. Over-expression leads to improvement.[34][30]
This protein has also been implicated in the integrity of cartilage. Out of all known nuclear receptors, Rev-erbα is the most highly expressed in osteoarthritic cartilage.[35] One study found that in patients with osteoarthritis has reduced Rev-erbα levels compared to normal cartilage.[36] Research on rheumatoid arthritis (RA) has implicated the potential for treatment with Rev-erbα agonists to RA patients due to their suppression of bone and cartilage destruction.[37]
Rev-erbα contributes to the inflammatory response in mammals.[34] In mouse smooth muscle cells, the protein up-regulates expression ofinterleukin 6 (IL-6) andcyclooxygenase-2. In humans, it controls thelipopolysaccharide (LPS) inducedendotoxic response through repressingtoll-like receptor (TLR-4), which triggers the immune response to LPS.[28][34] In the brain, Rev-erbα deletion causes a disruption in the oscillation ofmicroglial activation and increases the expression of pro-inflammatory transcripts.[19]
Many immune and inflammatory proteins exhibit circadian oscillatory behavior, and research has shown that Rev-erbα deficient mice no longer exhibit these oscillations, notably inIL-6,IL-12,CCL5, andCXCL1, andCCL2.[38] Rev-erbα has also been implicated in the development ofgroup 3 innate lymphoid cells (ILC3), which play a role in regulating intestinal health and are responsible for lymphoid development. REV-ERBα promotesRORγt expression, and RORγt is required for ILC3 expression. Rev-erbα is highly expressed in ILC3 subsets.[39]
Rev-erbα has been implicated in the regulation of memory and mood. Rev-erbα knockout mice are deficient in short term, long term, and contextual memories, showing deficits in the function of theirhippocampus.[40] In addition, Rev-erbα has been proposed to play a role in the regulation of midbraindopamine production and mood-related behavior in mice through repression oftyrosine hydroxylase gene transcription.[41] Dopamine related dysfunction is associated with mood disorders, notablymajor depressive disorder,seasonal affective disorder, andbipolar disorder. Genetic variations in humanNR1D1 loci are also associated with bipolar disorder onset.[41]
Rev-erbα has been proposed as a target in the treatment of bipolar disorder throughlithium, which indirectly regulates the protein at a post-translational level. Lithium inhibitsglycogen synthase kinase (GSK 3β), an enzyme that phosphorylates and stabilizes Rev-erbα. Lithium binding to GSK 3β then destabilizes and alters the function of Rev-erbα.[41] This research has been implicated in the development of therapeutic agents for affective disorders, such as lithium for bipolar disorder.[30]
^abMiyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, et al. (April 1989). "Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus".Cell.57 (1):31–9.doi:10.1016/0092-8674(89)90169-4.PMID2539258.S2CID19135678.
^Koh YS, Moore DD (April 1999). "Linkage of the nuclear hormone receptor genes NR1D2, THRB, and RARB: evidence for an ancient, large-scale duplication".Genomics.57 (2):289–92.doi:10.1006/geno.1998.5683.PMID10198169.
^Hastings MH, Maywood ES, Brancaccio M (August 2018). "Generation of circadian rhythms in the suprachiasmatic nucleus".Nature Reviews. Neuroscience.19 (8):453–469.doi:10.1038/s41583-018-0026-z.PMID29934559.S2CID49357675.
^abcdLazar MA (2016). "Rev-erbs: Integrating Metabolism Around the Clock". In Sassone-Corsi P, Christen Y (eds.).A Time for Metabolism and Hormones. Research and Perspectives in Endocrine Interactions. Cham: Springer International Publishing. pp. 63–70.doi:10.1007/978-3-319-27069-2_7.ISBN978-3-319-27068-5.PMID28892343.
^Marks R (2018). "Circadian Clock: Potential Role in Cartilage Integrity and Disruption".International Journal of Orthopaedics.5 (4):936–942.doi:10.17554/j.issn.2311-5106.2018.05.280 (inactive 13 November 2025).ISSN2311-5106.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, et al. (Apr 1989). "Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus".Cell.57 (1):31–9.doi:10.1016/0092-8674(89)90169-4.PMID2539258.S2CID19135678.
Sierk ML, Zhao Q, Rastinejad F (Oct 2001). "DNA deformability as a recognition feature in the reverb response element".Biochemistry.40 (43):12833–43.doi:10.1021/bi011086r.PMID11669620.
