NR1D2
Description
The NR1D2 (nuclear receptor subfamily 1 group D member 2) is a protein-coding gene located on chromosome 3.
Rev-Erb beta (Rev-Erbβ), also known as nuclear receptor subfamily 1 group D member 2 (NR1D2), is a member of the Rev-Erb protein family. Rev-Erbβ, like Rev-Erbα, belongs to the nuclear receptor superfamily of transcription factors and can modulate gene expression through binding to gene promoters. Together with Rev-Erbα, Rev-Erbβ functions as a major regulator of the circadian clock. These two proteins are partially redundant. 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. This gene is expressed in the central and peripheral nervous system, spleen, mandibular maxillary processes, and blood islands. Rev-Erbβ plays a major role in the conduction of inductive signals to aid in controlling differentiating neurons.
== Discovery == Rev-Erbβ was discovered in 1994, when B. Dumas et al. isolated its cDNA, naming the new receptor BD73.
NR1D2 is a transcriptional repressor that regulates circadian rhythm and metabolic pathways in a heme-dependent manner. It is an integral component of the circadian clock, directly repressing the expression of core clock components BMAL1 and CLOCK. It also regulates genes involved in lipid metabolism and the inflammatory response. NR1D2 acts as a receptor for heme, which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. It recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers. It binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). NR1D2 acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. It regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis, including CD36, FABP3, FABP4, UCP3, SCD1, and MSTN. It regulates hepatic lipid metabolism via the repression of APOC3. NR1D2 represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, NR1D2 can also act as a transcriptional activator. It acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle. NR1D2 plays a role in the regulation of circadian sleep/wake cycle and is essential for maintaining wakefulness during the dark phase or active period. It is a key regulator of skeletal muscle mitochondrial function, negatively regulating the skeletal muscle expression of core clock genes and genes involved in mitochondrial biogenesis, fatty acid beta-oxidation, and lipid metabolism. It may play a role in the circadian control of neutrophilic inflammation in the lung. NR1D2 binds DNA as a monomer or a homodimer. It interacts with NCOA5 coactivator, leading to a strong increase of transcription of target genes. It interacts (via N-terminus) with KAT5 and (via C-terminus) with HDAC1. It also interacts with ZNHIT1 and SIAH2.
NR1D2 is also known as BD73, EAR-1R, REVERBB, REVERBbeta, RVR.
