NR1D1 (Nuclear Receptor Subfamily 1 Group D Member 1), also known as REV-ERBalpha, is a nuclear receptor protein that functions as a transcriptional repressor. It plays a critical role in regulating circadian rhythm and metabolism. NR1D1 is encoded by the NR1D1 gene located on chromosome 17q11.2. The protein is a member of the nuclear receptor superfamily and acts as a key component of the molecular circadian clock.
<div class="infobox infobox-gene"> <table> <tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">NR1D1 — Nuclear Receptor Subfamily 1 Group D Member 1</th></tr> <tr><td><strong>Gene Symbol</strong></td><td>NR1D1</td></tr> <tr><td><strong>Full Name</strong></td><td>NR1D1 — Nuclear Receptor Subfamily 1 Group D Member 1</td></tr> <tr><td><strong>Chromosome</strong></td><td>17q11.2</td></tr> <tr><td><strong>NCBI Gene ID</strong></td><td>[9973](https://www.ncbi.nlm.nih.gov/gene/9973)</td></tr> <tr><td><strong>OMIM</strong></td><td>[602437](https://www.omim.org/entry/602437)</td></tr> <tr><td><strong>Ensembl ID</strong></td><td>ENSG00000156395</td></tr> <tr><td><strong>UniProt ID</strong></td><td>[Q9UH73](https://www.uniprot.org/uniprot/Q9UH73)</td></tr> <tr><td><strong>Associated Diseases</strong></td><td>Circadian rhythm disorders, metabolic disorders, neurodegeneration</td></tr> </table> </div>
Function
NR1D1 (REV-ERBα) is a nuclear receptor and transcriptional repressor that is a key component of the circadian clock. It represses expression of core clock genes and metabolic genes in a circadian manner.
Disease Associations
NR1D1 dysregulation has been implicated in metabolic syndrome and neurodegenerative diseases. REV-ERB agonists show neuroprotective effects in animal models[@sulli2019][@cho2020].
Alzheimer's Disease
Circadian disruption: AD patients commonly exhibit circadian rhythm disturbances
Amyloid metabolism: REV-ERB regulates genes involved in amyloid precursor protein (APP) processing
Neuroinflammation: NR1D1 modulates inflammatory responses in the brain
Evidence: NR1D1 expression is altered in AD patient brains[@huang2021]
Parkinson's Disease
Circadian dysfunction: PD patients show disrupted circadian rhythms
Mitochondrial function: NR1D1 regulates genes involved in mitochondrial biogenesis
Evidence: Circadian clock genes show altered expression in PD substantia nigra[@musiek2020]
Metabolic Disorders
Obesity: REV-ERB agonists reduce adipogenesis
Diabetes: Metabolic regulation throughNR1D1
Dyslipidemia: Lipid metabolism effects
Mechanism of Action
Transcriptional Repression
NR1D1 represses gene transcription by:
Binding to REV-ERB response elements (RRE) in target gene promoters
Recruiting co-repressor complexes (NCoR/HDAC3)
Repressing core clock genes (BMAL1, CLOCK) and metabolic genes
Circadian Rhythm Regulation
Core component: Part of the transcriptional-translational feedback loop
Rhythmic expression: NR1D1 peaks during daytime in mice
Target genes: Controls metabolism, inflammation, and neuronal function
Therapeutic Implications
REV-ERB Agonists
Synthetic REV-ERB agonists (e.g., SR9009, SR9011) show promise for:
| Application | Mechanism | Status | |-------------|-----------|--------| | Neuroprotection | Reduce neuroinflammation | Preclinical[@yin2022] | | Metabolic benefit | Improve mitochondrial function | Phase I trials | | Anti-aging | Enhance autophagy | Research |
Drug Development
Small molecule agonists: SR9009, SR9011
Combination therapy: With other circadian modulators
Timing: Circadian timing affects drug efficacy
Expression
Expressed in most tissues with circadian oscillation. In brain, expressed in hypothalamus, [cortex](/brain-regions/cortex), and [hippocampus](/brain-regions/hippocampus).
Key Publications
[Sulli et al., REV-ERB in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30601726/)
[Cho et al., NR1D1 and metabolic disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32029631/)
[Huang et al., Circadian clock and Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Musiek et al., Circadian rhythm genes in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)
[Yin et al., REV-ERB agonists as neuroprotective agents (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
See Also
[REV-ERBα Protein](/proteins/nr1d1-protein)
[Circadian Rhythm and Neurodegeneration](/mechanisms/circadian-neurodegeneration)
[Sulli et al., REV-ERB in neurodegeneration (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30601726/)
[Cho et al., NR1D1 and metabolic disease (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32029631/)
[Huang et al., Circadian clock and Alzheimer's disease (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Musiek et al., Circadian rhythm genes in Parkinson's disease (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)
[Yin et al., REV-ERB agonists as neuroprotective agents (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
Pathway Diagram
The following diagram shows the key molecular relationships involving NR1D1 — Nuclear Receptor Subfamily 1 Group D Member 1 (REV-ERBα) discovered through SciDEX knowledge graph analysis: