brain, liver, skeletal muscle, and adipose tissue. Comparison of the human NR1D2 sequence with other species indicates a high level of conservation across animals, with 472 discovered orthologs, including in mice, chickens, lizards, and zebrafish. Similarly to NR1D1, this suggests NR1D2 was present in the most recent common animal ancestor. NR1D2 has only one paralog in humans, the NR1D1 gene, which is located on chromosome 17, but it is closely related to other members of the nuclear receptor family and is functionally related to other nuclear receptor genes, such as thyroid hormone receptor beta (THRB), peroxisome proliferator activated receptor delta (PPARD), and retinoic acid receptor beta (RARB). Linkage analysis reveals that NR1D2 and THRB are highly linked due to proximity on chromosome 3, and that they are both linked to RARB. Combined with the linkage between the NR1D1/THRA locus and the RARA gene, this suggests that these two gene clusters arose from a duplication event. Structure The human NR1D2 gene produces a protein product (REV-ERBβ) of 579 amino acids. Rev-Erbβ is similar to Rev-Erbα in both its structure and mechanism of transcriptional repression. Like Rev-Erbα, Rev-Erbβ has 3 major functional domains which are common to nuclear receptor proteins, including a DNA-binding domain (DBD) and a ligand-binding domain (LBD) at the C-terminus, which are highly conserved in Rev-Erb orthologs, and a N-terminus domain which allows for activity modulation. Much like Rev-Erbα, Rev-Erbβ can bind to two classes of DNA response elements via its DBD, which contains two C4-type zinc fingers. These two classes include a DNA sequence commonly referred to as RORE due to its interaction with the transcriptional activator Retinoic Acid Receptor-related Orphan Receptor (ROR) and a direct repeat 2 element of RORE known as RevDR2. 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, the Rev-Erbs can repress transcription as a monomer through competitive binding at single RORE elements by preventing the binding of constitutive transcription activator ROR or as a homodimer through binding to RevDR2 sites. The Rev-Erb homodimer is required for its interaction with Nuclear Receptor Co-Repressor (NCoR), or more weakly, with Silencing Mediator of Retinoid and Thyroid Receptors (SMRT). The interaction with NCoR is stabilized by interaction with heme, which binds the to the Rev-Erb ligand-binding pocket. Rev-Erbβ undergoes a