Rev-ErbA alpha
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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 molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
. 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 A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time. Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...
through repression of the positive clock element
Bmal1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...
. It also regulates several physiological processes under circadian control, including
metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
and
immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
pathways. Rev-Erbɑ
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
demonstrates circadian oscillation in its expression, and it is highly expressed in mammals in the
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
and metabolic tissues such as
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
,
adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
, and
liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
.


Discovery

Rev-Erbɑ was discovered in 1989 by Nobuyuki Miyajima and colleagues, who identified two ''erbA''
homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same locus (genetics), loci where they pr ...
on human
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
that were transcribed from opposite DNA strands in the same
locus Locus (plural loci) is Latin for "place". It may refer to: Entertainment * Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front * ''Locus'' (magazine), science fiction and fantasy magazine ** ''Locus Award' ...
. One of the
genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
encoded a protein that was highly similar to chicken
thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have ...
, 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 In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a spe ...
from a human fetal skeletal muscle
library A library is a collection of materials, books or media that are accessible for use and not just for display purposes. A library provides physical (hard copies) or digital access (soft copies) materials, and may be a physical location or a vir ...
. 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 A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
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 Positive is a property of positivity and may refer to: Mathematics and science * Positive formula, a logical formula not containing negation * Positive number, a number that is greater than 0 * Plus sign, the sign "+" used to indicate a posit ...
and negative loops of the TTFL.


Genetics and evolution

The ''NR1D1'' (nuclear receptor subfamily 1 group D member 1) gene, located on
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
, 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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
, forming only 1
splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...
. The NR1D1 promoter itself contains a REV-ERB
response element Response elements are short sequences of DNA within a gene Promoter (genetics), promoter or Enhancer (genetics), enhancer region that are able to bind specific transcription factors and regulate Transcription (genetics), transcription of genes. Und ...
(RevRE), which allows for regulation of gene expression both through
autoregulation Autoregulation is a process within many biological systems, resulting from an internal adaptive mechanism that works to adjust (or mitigate) that system's response to stimuli. While most systems of the body show some degree of autoregulation, it ...
and regulation by retinoic acid receptor-related orphan receptor alpha (RORɑ), another nuclear receptor transcription factor. ''NR1D1'' also contains an
E-box An E-box (enhancer box) is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG (where N can b ...
at its promoter, which allows for regulation by
BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...
. In humans, ''NR1D1'' (REV-ERBɑ) is highly expressed in the brain and metabolic tissues, including skeletal muscle, adipose tissue, and the liver.
Genomic Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
analysis suggests that the ''NR1D1'' gene was present in the
most recent common ancestor In biology and genetic genealogy, the most recent common ancestor (MRCA), also known as the last common ancestor (LCA) or concestor, of a set of organisms is the most recent individual from which all the organisms of the set are descended. The ...
of all animals, with
orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
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 Conservation is the preservation or efficient use of resources, or the conservation of various quantities under physical laws. Conservation may also refer to: Environment and natural resources * Nature conservation, the protection and managem ...
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 Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
, NR1D2 ( REV-ERBβ), which is located on
chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
. REV-ERBα has 3 major functional domains, including a
DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
(DBD) and a
ligand-binding domain In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
(LBD) at the C-terminus, and a
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
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 A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...
in the C-terminal that is necessary for
coactivator A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA p ...
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 Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consisti ...
, an
endogenous ligand In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...
of Rev-Erbα, further stabilizes the interaction with NCoR. The repression by Rev-Erbα also requires interaction with the class I histone deacteylase 3 (HDAC3) - NCoR complex. The
catalytic activity Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
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 Major (commandant in certain jurisdictions) is a military rank of commissioned officer status, with corresponding ranks existing in many military forces throughout the world. When used unhyphenated and in conjunction with no other indicators ...
of this sequence via its DBD domain, which contains two C4-type zinc fingers. Rev-Erbα can repress gene activation as a
monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...
through
competitive binding Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...
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 Response elements are short sequences of DNA within a gene Promoter (genetics), promoter or Enhancer (genetics), enhancer region that are able to bind specific transcription factors and regulate Transcription (genetics), transcription of genes. Und ...
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 In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
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


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 A clock or a timepiece is a device used to measure and indicate time. The clock is one of the oldest human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month and the ...
and
BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less com ...
that contribute to the rhythmic expression of genes within this loop, notably ''
per Per is a Latin preposition which means "through" or "for each", as in per capita. Per or PER may also refer to: Places * IOC country code for Peru * Pér, a village in Hungary * Chapman code for Perthshire, historic county in Scotland Math ...
'' and ''
cry Crying is the dropping of tears (or welling of tears in the eyes) in response to an emotional state, or pain. Emotions that can lead to crying include sadness, anger, and even happiness. The act of crying has been defined as "a complex secreto ...
''. The expression of these genes then act through negative feedback to inhibit CLOCK:BMAL1 transcription. 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. 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 suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
, 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.


Metabolism

Rev-erbα plays a role in the regulation of whole body metabolism through controlling
lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
, bile acid metabolism, and
glucose metabolism Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms. Carbohydrates are central to many essential metabolic pathways. Plants ...
. 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. Rev-erbα regulates the expression of liver
apolipoproteins Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. The lipid components of lipoproteins a ...
,
sterol regulatory element binding protein Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes ''SREBF1'' and ''SREBF2''. SREBPs belong to the basic-h ...
, and the fatty acid elongase ''elovl3'' through its repressional activity In addition, the silencing of Rev-erbα is associated with the reduction of fatty acid synthase, a key regulator of
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...
. Rev-erbα deficient mice exhibit
dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...
due to elevated triglyceride levels and Rev-erbα polymorphisms in humans have been associated with obesity. Rev-erbα also regulates
adipogenesis Adipogenesis is the formation of adipocytes (fat cells) from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as preadipocy ...
of white and brown adipocytes. Rev-Erbα transcription is induced during the adipogenic process, and over-expression of Rev-erbα enhances adipogenesis. Researchers have proposed that Rev-erbα's role in adipocyte function may affect the timing of processes such as lipid storage and lipolysis, contributing to long term issues with BMI control. Rev-erbα also regulates bile acid metabolism by indirectly down-regulating ''
Cyp7A1 Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enz ...
'', which encodes the first and rate controlling enzyme of the major bile acid biosynthetic pathway. 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. 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 Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development o ...
through interaction with the transcription complex Nuclear Factor-T. 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. 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. 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. In mouse smooth muscle cells, the protein up-regulates expression of interleukin 6 (IL-6) and
cyclooxygenase-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene. ...
. In humans, it controls the
lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
(LPS) induced endotoxic response through repressing toll-like receptor (TLR-4), which triggers the immune response to LPS. In the brain, Rev-erbα deletion causes a disruption in the oscillation of microglial activation and increases the expression of pro-inflammatory transcripts. 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 IL-6, IL-12,
CCL5 Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTE ...
, and
CXCL1 The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infecti ...
, and
CCL2 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL ...
. 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 The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
. In addition, Rev-erbα has been proposed to play a role in the regulation of midbrain
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
production and mood-related behavior in mice through repression of
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
gene transcription. Dopamine related dysfunction is associated with mood disorders, notably
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
,
seasonal affective disorder Seasonal affective disorder (SAD) is a mood disorder subset, in which people who have normal mental health throughout most of the year exhibit depressive symptoms at the same time each year. Common symptoms include sleeping too much, having li ...
, and
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
. 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 Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...
, 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


Further reading

* * * * * * * * * * * * * * * * *


External links

* {{Receptor/signaling modulators Intracellular receptors Transcription factors