Rev-Erb beta (Rev-Erbβ), also known as nuclear receptor subfamily 1 group D member 2 (NR1D2), is a member of theRev-Erbprotein family. Rev-Erbβ, likeRev-Erbα, belongs to the nuclear receptor superfamily of transcription factors and can modulate gene expression through binding to gene promoters.[5] Together with Rev-Erbα, Rev-Erbβ functions as a major regulator of thecircadian clock. These two proteins are partially redundant.[6] Current research suggests that Rev-Erbβ is less important in maintaining the circadian clock than Rev-Erbα; knock-out studies of Rev-Erbα result in significant circadian disruption but the same has not been found with Rev-Erbβ. Rev-Erbβ compensation for Rev-Erbα varies across tissues, and further research is needed to elucidate the separate role of Rev-Erbβ.[7]
This gene is expressed in the central andperipheral nervous system,spleen,mandibular maxillary processes, andblood islands. Rev-Erbβ plays a major role in the conduction of inductive signals to aid in controlling differentiatingneurons.[5]
Rev-Erbβ was discovered in 1994, when B. Dumas et al. isolated itscDNA, naming the new receptor BD73.[5] The name Rev-Erbβ was coined a few months later in a paper by Eva Enmark, Tommi Kainu, Markku Tapio Pelto-Huikko, and Jan Ǻke Gustafsson where they isolatedRev-Erb alphacDNA in a rat brain.[8]
A new isoform of Rev-Erbβ, named Rev-Erbβ 2, was discovered using ratcDNA a few months later in 1995 by N. Giambiagi and colleagues.[7] They found it to be identical to Rev-Erbβ 1, except that the Rev-Erbβ 1 protein is 195amino acids longer than Rev-Erbβ 2. However, further research has indicated that the discovered Rev-Erbβ 2cDNA was likely a splice variant of the Nr1d2 gene that arose through alternative splicing and the use of a differentpolyadenylation site.
Inmammals, theNR1D2 (nuclear receptor subfamily 1 group D member 2)gene encodes the protein Rev-Erbβ. UnlikeNR1D1, the strand oppositeNR1D2 does not have any significant reading frames, and the gene is located on the forward strand ofchromosome 3.[9] Despite their different locations, theNR1D1 andNR1D2 genes are highly homologous and are paralogs within thegenome.[5] In humans, theNR1D2 gene itself contains 10 exons which form 5 splice variants (NR1D2-201 - NR1D2-205), ranging from 5231 base pairs (NR1D2-201) to 600 base pairs (NR1D2-204). However, only NR1D2-201 produces a functional protein. In mammals,NR1D2 (Rev-Erbβ) is expressed throughout the body and with high expression in several tissues, including thebrain,liver,skeletal muscle, andadipose tissue.[9]
Comparison of the humanNR1D2 sequence with otherspecies indicates a high level of conservation across animals, with 472 discovered orthologs, including inmice,chickens,lizards, andzebrafish. Similarly toNR1D1, this suggestsNR1D2 was present in the most recent commonanimal ancestor.NR1D2 has only one paralog inhumans, theNR1D1 gene, which is located onchromosome 17, but it is closely related to other members of the nuclear receptor family and is functionally related to other nuclear receptor genes, such asthyroid hormone receptor beta (THRB),peroxisome proliferator activated receptor delta (PPARD), andretinoic acid receptor beta (RARB). Linkage analysis reveals thatNR1D2 andTHRB are highly linked due to proximity on chromosome 3, and that they are both linked toRARB. Combined with the linkage between theNR1D1/THRA locus and theRARA gene, this suggests that these twogene clusters arose from a duplication event.[10]
The human NR1D2 gene produces a protein product (REV-ERBβ) of 579amino acids. Rev-Erbβ is similar to Rev-Erbα in both its structure and mechanism oftranscriptional repression. Like Rev-Erbα, Rev-Erbβ has 3 major functional domains which are common to nuclear receptor proteins, including aDNA-binding domain (DBD) and aligand-binding domain (LBD) at theC-terminus, which are highly conserved in Rev-Erb orthologs, and aN-terminus domain which allows for activity modulation.[11]
Much like Rev-Erbα, Rev-Erbβ can bind to two classes ofDNA response elements via its DBD, which contains two C4-type zinc fingers.[12] These two classes include a DNA sequence commonly referred to as RORE due to its interaction with the transcriptional activator Retinoic Acid Receptor-related Orphan Receptor (ROR) and a direct repeat 2 element of RORE known as RevDR2.[13] The Rev-Erb proteins are unique from other nuclear receptors in that they do not have ahelix in the C-terminal that is necessary for coactivator recruitment and activation by nuclear receptors via their LBD. Instead, the Rev-Erbs can repress transcription as amonomer through competitive binding at single RORE elements by preventing the binding of constitutive transcription activator ROR or as ahomodimer through binding to RevDR2 sites.[14] The Rev-Erbhomodimer is required for its interaction withNuclear Receptor Co-Repressor (NCoR), or more weakly, with Silencing Mediator of Retinoid and Thyroid Receptors (SMRT). The interaction with NCoR is stabilized by interaction withheme, which binds the[clarification needed] to the Rev-Erbligand-binding pocket. Rev-Erbβ undergoes a conformational change when complexed with heme, as its structure shows that helices 3,7, and 11 move to enlarge the ligand binding pocket in order to accommodateheme. The repression by Rev-Erb proteins also requires interaction of class Ihistone deacetylase 3 (HDAC3) with NCoR, which results in gene repression via histone deacetylation.[12]
Rev-Erbβ binds togenomic Rev-Erbα-binding sites that have adiurnal profile identical or similar to Rev-Erbα. Thisprotein also helps maintain clock andmetabolic gene regulation and protects system functioning when Rev-Erbα is missing. Rev-Erbβ compensates for loss of function frommetabolic distress in the case that Rev-Erbα is lost. Theliver and metabolic processes can still run when Rev-Erbα is missing and Rev-Erbβ is present. Losing both Rev-Erbα and Rev-Erbβ causes cells to become arrhythmic.[15]
When Rev-Erbβ is missing, there can be significant change in performance ofmetabolic activity with drastic effects. For example:
Rev-Erbβ plays a role in blocking thetrans-activation of retinoic acid-related orphan receptor-α (RORα). RORα is involved in the regulation oflipoproteincholesterol,lipidhomeostasis, andinflammation. Rev-Erbβ and RORα are both expressed in similar tissues, such asskeletal muscle. They have similar expression patterns, target genes, and cognate sequences within the skeletal muscle. Rev-Erbβ causes several genes assisting inlipid absorption to decrease expression. Rev-Erbβ controls lipid and energyhomoeostasis inskeletal muscle. Rev-Erbβ may be useful in therapeutic treatments ofdyslipidemia and regulatingmuscle growth.[16]
Rev-Erbβ is also a circadian regulated gene; itsmRNA displays rhythmic expression in vivo and in serum-synchronizedcell cultures. However, it is currently unknown to what extent Rev-Erbβ contributes to oscillations of the core circadian clock. However it has been shown that heme suppresseshepaticgluconeogenic gene expression and glucose output through the related Rev-Erbα receptor which mediates gene repression. Hence, the Rev-Erbαreceptor detects heme and thereby coordinates the cellular clock,glucosehomeostasis, and energymetabolism.[17]
Rev-Erbβ plays a role inskeletal musclemitochondrial biogenesis. Originally Rev-Erbβ was thought to be functionally redundant of Rev-Erbα but recent findings prove that there are subtle differences. Rev-Erbβligands may be used in the treatment of metabolic disorders, likemetabolic syndrome. It has control ofskeletal muscle metabolism and energy that can be beneficial in treatment options.[18]
Rev-Erbβ gene contributes to the downstream regulation of clock output genes by generating specificKOmutants. It is still unknown all of the functions Rev-Erbβ has in the core circadian clock and exactly how it differs from Rev-Erbα.
PDB gallery | |
|---|---|
|
