Rev-ErbA alpha

Nuclear receptor subfamily 1, group D, member 1
The DNA binding domain of NR1D1 bound to double stranded DNA.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1A6Y​, 1EF6​, 1GA5​, 1HLZ​, 3N00​
Identifiers
Symbols	NR1D1 ; EAR1; THRA1; THRAL; ear-1; hRev
External IDs	OMIM: 602408 MGI: 2444210 HomoloGene: 23324 IUPHAR: 596 GeneCards: NR1D1 Gene
Gene ontology Molecular function • RNA polymerase II regulatory region sequence-specific DNA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding • core promoter sequence-specific DNA binding • transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding • transcription corepressor binding • steroid hormone receptor activity • transcription corepressor activity • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding • protein binding • zinc ion binding • heme binding • transcription regulatory region DNA binding Cellular component • nuclear chromatin • nucleus • nucleoplasm • cytoplasm • dendrite • dendritic spine Biological process • negative regulation of transcription from RNA polymerase II promoter • glycogen biosynthetic process • transcription initiation from RNA polymerase II promoter • circadian rhythm • gene expression • proteasomal protein catabolic process • negative regulation of receptor biosynthetic process • regulation of lipid metabolic process • cell differentiation • intracellular receptor signaling pathway • circadian regulation of gene expression • negative regulation of toll-like receptor 4 signaling pathway • regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter • regulation of circadian rhythm • steroid hormone mediated signaling pathway • response to leptin • regulation of fat cell differentiation • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • circadian temperature homeostasis • regulation of insulin secretion involved in cellular response to glucose stimulus • regulation of type B pancreatic cell proliferation • positive regulation of bile acid biosynthetic process • cellular response to lipopolysaccharide • regulation of cholesterol homeostasis • positive regulation of cholesterol homeostasis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9572	217166
Ensembl	ENSG00000126368	ENSMUSG00000020889
UniProt	P20393	Q3UV55
RefSeq (mRNA)	NM_021724	NM_145434
RefSeq (protein)	NP_068370	NP_663409
Location (UCSC)	Chr 17: 40.09 – 40.1 Mb	Chr 11: 98.77 – 98.78 Mb
PubMed search

Rev-ErbA alpha also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1), is a protein that in humans is encoded by the NR1D1 gene.^[2]

Rev-erbα is member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor.^[3] In mammals, Rev-erbα is highly expressed in the liver, skeletal muscle, adipose tissue, and the brain, participating in the development and circadian regulation of these tissues.^[4][5]

Gene and protein structure

Rev-erbα is transcribed from the opposite strand of the thyroid receptor α (c-erbAα) gene on chromosome 17, with a 269-nucleotide overlap between the two transcripts.^[3] The other mammalian isoform of the receptor, Rev-erbβ is encoded by another gene on chromosome 3. In addition, there is one non-mammalian homolog, the ecdysone-regulated gene E75, which is present in Drosophila and C. elegans. The Rev-erbα gene itself has multiple transcripts. Two promoters govern the expression of the Rev-erbα gene in human and rat, generating two mRNA isoforms. The full-length isoform encodes a 614-amino acid protein, while a second isoform is generated from an internal promoter and produces a protein that is shorter by 106 amino acids. Both Rev-erbα mRNA isoforms contain E-boxes as well as Rev-erbα response elements, which means that they can be regulated in a circadian manner by the BMAL and Rev-erba proteins. In fact, both transcripts exhibit rhythmic expression in serum-synchronized fibroblasts.

The Rev-erbα protein is structurally unique from other nuclear receptors, in that it lacks helix 12 (H12) in its ligand-binding domain, which is usually responsible for forming the ligand binding pocket in other nuclear receptors. In place of the missing H12, Rev-erbα displays a hydrophobic interface that binds the corepressor N-CoR, making it a potent transcriptional repressor.^[6] Interestingly, all members of the Rev-erb family bind heme, which may act as a ligand to regulate their transcriptional activity.^[7]

Physiologic function

Rev-erbα regulates gene transcription by directly binding to target response elements (RevREs), and comprises an A/T-rich flank followed by AGGTCA. Rev-erbα mediates repression by recruiting the corepressor N-CoR, which then activates the histone deacetylase (HDAC) 3. A number of target genes have been identified for Rev-erbα, including the lipoproteins ApoA1 and ApoCIII, hydratase dehydrogenase, the circadian factor BMAL, and the anti-fibrinolytic factor PAI-1.^[8] Many of these genes are coordinately regulated by Rev-erbα and the RAR-related orphan receptor RORα, which share the same response elements but exert opposite effects on gene transcription. Crosstalk between Rev-erbα and RORα likely acts to fine-tune their target physiologic networks, such as circadian rhythms, metabolic homeostasis,^[9] and inflammation.^[10]

Rev-erbα mRNA is induced during adipogenesis and is highly expressed in adipose tissue.^[11] One study reported that overexpression of Rev-erbα may enhance adipogenesis in cultured mouse adipocytes, but the mechanism of this effect remains to be elucidated.^[12] More recently, a study showed that the deletion of Rev-erbα in mice alters glucose and lipid metabolism and leads to obesity.^[13]

Rev-erbα expression is also regulated at the post-translational level: it is phosphorylated on the amino terminus by glycogen synthase kinase (GSK 3β), which contributes to its protein stability. It has been shown that lithium, which inhibits GSK3β, can de-stabilize Rev-erbα protein and affect its function in the circadian clock.^[14] This may partly explain lithium’s therapeutic effect on circadian diseases such as bipolar disorder.

References

Further reading

External links

• NR1D1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery 1a6y: REVERBA ORPHAN NUCLEAR RECEPTOR/DNA COMPLEX  1ga5: CRYSTAL STRUCTURE OF THE ORPHAN NUCLEAR RECEPTOR REV-ERB(ALPHA) DNA-BINDING DOMAIN BOUND TO ITS COGNATE RESPONSE ELEMENT  1hlz: CRYSTAL STRUCTURE OF THE ORPHAN NUCLEAR RECEPTOR REV-ERB(ALPHA) DNA-BINDING DOMAIN BOUND TO ITS COGNATE RESPONSE ELEMENT