Rev-ErbA alpha

Source: Wikipedia, the free encyclopedia.
NR1D1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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 MbChr 11: 98.66 – 98.67 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

Rev-Erbɑ plays an important role in regulation of the core

Bmal1. It also regulates several physiological processes under circadian control, including metabolic and immune pathways.[6][7] 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.[6][8]

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.[9] 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).[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 rat fibroblasts showed daily rhythms.[11] 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.[12]

Genetics and evolution

The NR1D1 (nuclear receptor subfamily 1 group D member 1) gene, located on

BMAL1. In humans, NR1D1 (REV-ERBɑ) is highly expressed in the brain and metabolic tissues, including skeletal muscle, adipose tissue, and the liver.[8][6]

duplication event.[14] 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).[13] Furthermore, studies have shown that the NR1D1/THRA genetic locus is genetically linked to the RARA gene.[6][15]

Protein structure

The human NR1D1 gene produces a protein product (REV-ERBα) of 614

ligand-binding domain (LBD) at the C-terminus, and a N-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 a

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).[18]

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.[19][20]

Function

REV‑ERBα regulates clock-controlled genes (CCGs) to affect physiological processes in various tissues.

Circadian oscillator

Rev-Erbα has been proposed to coordinate circadian metabolic responses.

BMAL1 that contribute to the rhythmic expression of genes within this loop, notably per and cry.[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 with Rev-Erbβ and the orphan receptor RORα, 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 of NR1D1, 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 the suprachiasmatic 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]

Metabolism

Rev-erbα plays a role in the regulation of whole body metabolism through controlling

glucose 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 liver

Cyp7A1, 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 of α-cells and β-cells, which produce glucagon and insulin, respectively.[34]

Muscle and cartilage

Rev-erbα plays a role in myogenesis through interaction with the transcription complex Nuclear 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]

Immune system

Rev-erbα contributes to the inflammatory response in mammals.

endotoxic response through repressing toll-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 of microglial 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 in

RORγt expression, and RORγt is required for ILC3 expression. Rev-erbα is highly expressed in ILC3 subsets.[39]

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.[40] 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.[41] 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.[41]

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.[41] This research has been implicated in the development of therapeutic agents for affective disorders, such as lithium for bipolar disorder.[30]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000126368 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020889 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c "NR1D1 Gene | NR1D1 Protein | NR1D1 Antibody". GeneCards. Retrieved 2021-05-06.
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  11. S2CID 12445337
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  12. ^
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  13. ^
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  14. PMID 10198169
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  15. S2CID 43554925
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  17. ^ "HomoloGene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-05-06.
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  20. S2CID 30249508
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  21. ^
    PMID 19696364
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  22. PMID 26568119
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  23. S2CID 33279857
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  24. PMID 21526899
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  25. PMID 28765524
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  26. S2CID 49357675
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  27. S2CID 84204023
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  33. PMID 24944897
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  34. ^
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  35. ISSN 2311-5106
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  36. PMID 15761026
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  37. S2CID 82056456
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  38. PMID 23391992
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  39. PMID 31586012
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  41. ^
    S2CID 3334962
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Further reading

External links
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