Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the NR1D1 gene, which is highly conserved across animal species. Rev-Erbɑ plays an important role in regulation of the core circadian clock through repression of the positive clock element Bmal1. It also regulates several physiological processes under circadian control, including metabolic and immune pathways. Rev-Erbɑ mRNA demonstrates circadian oscillation in its expression, and it is highly expressed in mammals in the brain and metabolic tissues such as skeletal muscle, adipose tissue, and liver.
Discovery Rev-Erbɑ was discovered in 1989 by Nobuyuki Miyajima and colleagues, who identified two erbA homologs on human chromosome 17 that were transcribed from opposite DNA strands in the same locus. One of the genes encoded a protein that was highly similar to chicken thyroid hormone receptor, and the other, which they termed ear-1, would later be described as Rev-Erbɑ. The protein was first referenced by the name Rev-Erbɑ in 1990 by Mitchell A. Lazar, Karen E. Jones, and William W. Chin, who isolated Rev-Erbɑ complementary DNA from a human fetal skeletal muscle library. Similar to the gene in rats, they found that human Rev-Erbɑ was transcribed from the strand opposite human thyroid hormone receptor alpha (THRA, c-erbAα). 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 rat fibroblasts showed daily rhythms. Rev-Erbɑ was first identified as a key player in the transcription translation feedback loop (TTFL) in 2002, when experiments demonstrated that Rev-Erbɑ acted to repress transcription of the Bmal1 gene, and Rev-Erbɑ expression was controlled by other TTFL components. This established Rev-Erbɑ as the link between the positive and negative loops of the TTFL.
Genetics and evolution The NR1D1 (nuclear receptor subfamily 1 group D member 1) gene, located on chromosome 17, encodes the protein REV-ERBɑ in humans. It is transcribed from the opposite strand of the human thyroid hormone receptor alpha (THRA, c-erbAα) so that NR1D1 and THRA cDNA are complementary on 269 bases. The gene consists of 7,797 bases with 8 exons, forming only 1 splice variant. The NR1D1 promoter itself contains a REV-ERB response element (RevRE), which allows for regulation of gene expression both through autoregulation and regulation by retinoic acid receptor-related orphan receptor alpha (RORɑ), another nuclear receptor transcription factor. NR1D1 also contains an E-box at its promoter, which allows for regulation by BMAL1. In humans, NR1D1 (REV-ERBɑ) is highly expressed in the brain and metabolic tissues, including skeletal muscle, adipose tissue, and the liver. Genomic analysis suggests that the NR1D1 gene was present in the most recent common ancestor of all animals, with orthologs present in 378 species tested, including chimpanzees, dogs, mice, rats, chickens, zebrafish, frogs, and fruit flies. Comparison to the rat ortholog, Nr1d1, indicates high conservation in the DNA binding and carboxy-terminal domains, as well as conservation of transcription of c-erbA alpha-2 and Rev-Erbɑ on opposite strands. In humans, NR1D1 has only one paralog, NR1D2 (REV-ERBβ), which is located on chromosome 3 and likely arose from a duplication event. However, both NR1D1 and NR1D2 are members of the nuclear receptor family, indicating they share common ancestry. As such, NR1D1 is functionally related to other nuclear receptor genes, such as peroxisome proliferator activated receptor delta (PPARD) and retinoic acid receptor alpha (RARA). Furthermore, studies have shown that the NR1D1/THRA genetic locus is genetically linked to the RARA gene.
Protein structure The human NR1D1 gene produces a protein product (REV-ERBα) of 614 amino acids. REV-ERBα has 3 major functional domains, including a DNA-binding domain (DBD) and a ligand-binding domain (LBD) at the C-terminus, and a N-terminus domain which allows for activity modulation. These three domains are a common feature of nuclear receptor proteins. The Rev-Erb proteins are unique from other nuclear receptors in that they do not have a helix in the C-terminal that is necessary for coactivator recruitment and activation by nuclear receptors via their LBD. Instead, Rev-Erbα interacts via its LBD with Nuclear Receptor Co-Repressor (NCoR) and another closely related co-repressor Silencing Mediator of Retinoid and Thyroid Receptors (SMRT), although the interaction with NCoR is stronger due to its structural compatibility. Heme, an endogenous ligand of Rev-Erbα, further stabilizes the interaction with NCoR. The repression by Rev-Erbα also requires interaction with the class I histone deactylase 3 (HDAC3) - NCoR complex. The catalytic 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. It is still unknown whether other HDACs play a role in the function of Rev-Erbα. 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 activator Retinoic Acid Receptor-related Orphan Receptor (ROR). This sequence consists of an "AGGTCA" half-site preceded by an A/T sequence.. Rev-Erbα binds in the major groove of this sequence via its DBD domain, which contains two C4-type zinc fingers. Rev-Erbα can repress gene activation as a monomer through competitive 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 a response element that is a direct repeat of the RORE (RevDR2). In mice, it has been shown that the N-terminal regulatory domain contains an important site for phosphorylation by casein kinase 1 epsilon (Csnk1e), which aids in proper localization of Rev-Erbα, and furthermore, that this domain is necessary for activation of the gap junction protein 1 (GJA1) gene.
Function
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