Rev-ErbA alpha

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. 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. 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). == Protein structure ==

The human NR1D1 gene produces a protein product (REV-ERBα) of 614 amino acids. These three domains are a common feature of nuclear receptor proteins. 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. == Function ==

Circadian oscillator Rev-Erbα has been proposed to coordinate circadian metabolic responses. Circadian rhythms are driven by interlocking transcription/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 proteins CLOCK and BMAL1 that contribute to the rhythmic expression of genes within this loop, notably per and cry. The expression of these genes then act through negative feedback to inhibit CLOCK:BMAL1 transcription. 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. CLOCK:BMAL1 expression activates the transcription of NR1D1, encoding the Rev-Erbα protein. Increased Rev-Erbα expression in turn, represses transcription of BMAL1, stabilizing the loop. The oscillating expression of RORα and Rev-Erbα in the suprachiasmatic nucleus, the principal circadian timekeeper in mammals, 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. 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. In addition, the silencing of Rev-erbα is associated with the reduction of fatty acid synthase, a key regulator of lipogenesis. and Rev-erbα polymorphisms in humans have been associated with obesity. Rev-erbα also regulates adipogenesis of white and brown adipocytes. More directly, Rev-erbα's expression in the pancreas regulates the function of α-cells and β-cells, which produce glucagon and insulin, respectively. Muscle and cartilage Rev-erbα plays a role in myogenesis through interaction with the transcription complex Nuclear Factor-T. One study found that in patients with osteoarthritis has reduced Rev-erbα levels compared to normal cartilage. 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. Immune system Rev-erbα contributes to the inflammatory response in mammals. Rev-erbα has also been implicated in the development of group 3 innate lymphoid cells (ILC3), which play a role in regulating intestinal health and are responsible for lymphoid development. REV-ERBα promotes RORγt expression, and RORγt is required for ILC3 expression. Rev-erbα is highly expressed in ILC3 subsets. Mood and behavior 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 their hippocampus. In addition, Rev-erbα has been proposed to play a role in the regulation of midbrain dopamine production and mood-related behavior in mice through repression of tyrosine hydroxylase gene transcription. Dopamine related dysfunction is associated with mood disorders, notably major depressive disorder, seasonal affective disorder, and bipolar disorder. Genetic variations in human NR1D1 loci are also associated with bipolar disorder onset. Rev-erbα has been proposed as a target in the treatment of bipolar disorder through lithium, which indirectly regulates the protein at a post-translational level. Lithium inhibits glycogen 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. This research has been implicated in the development of therapeutic agents for affective disorders, such as lithium for bipolar disorder. == References ==