receptor-related orphan receptor alpha (RORɑ), another nuclear receptor transcription factor. NR1D1 also contains an E-box at its promoter, which allows for regulation by BMAL1. In humans, NR1D1 (REV-ERBɑ) is highly expressed in the brain and metabolic tissues, including skeletal muscle, adipose tissue, and the liver. Genomic analysis suggests that the NR1D1 gene was present in the most recent common ancestor of all animals, with orthologs 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 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, NR1D2 (REV-ERBβ), which is located on chromosome 3 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. REV-ERBα has 3 major functional domains, including a DNA-binding domain (DBD) and a ligand-binding domain (LBD) at the C-terminus, and a N-terminus 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 in the C-terminal that is necessary for coactivator 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, an endogenous ligand 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 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