conformational change when complexed with heme, as its structure shows that helices 3,7, and 11 move to enlarge the ligand binding pocket in order to accommodate heme. The repression by Rev-Erb proteins also requires interaction of class I histone deacetylase 3 (HDAC3) with NCoR, which results in gene repression via histone deacetylation. Function Circadian oscillator Rev-Erbβ binds to genomic Rev-Erbα-binding sites that have a diurnal profile identical or similar to Rev-Erbα. This protein also helps maintain clock and metabolic gene regulation and protects system functioning when Rev-Erbα is missing. Rev-Erbβ compensates for loss of function from metabolic distress in the case that Rev-Erbα is lost. The liver and metabolic processes can still run when Rev-Erbα is missing and Rev-Erbβ is present. Losing both Rev-Erbα and Rev-Erbβ causes cells to become arrhythmic. When Rev-Erbβ is missing, there can be significant change in performance of metabolic activity with drastic effects. For example: Rev-Erbβ deficiency causes a drastic difference in the coupled formation of circadian networks of gene expression, while core clock gene expression remains oscillating. Having neither Rev-Erbα or Rev-Erbβ does not affect expression rhythms of core clock genes but affects other rhythmically-expressed output genes. Rev-Erbβ deficiency does not change circadian expression rhythms of PER2. Metabolism Rev-Erbβ plays a role in blocking the trans-activation of retinoic acid-related orphan receptor-α (RORα). RORα is involved in the regulation of lipoprotein cholesterol, lipid homeostasis, and inflammation. Rev-Erbβ and RORα are both expressed in similar tissues, such as skeletal muscle. They have similar expression patterns, target genes, and cognate sequences within the skeletal muscle. Rev-Erbβ causes several genes assisting in lipid absorption to decrease expression. Rev-Erbβ controls lipid and energy homoeostasis in skeletal muscle. Rev-Erbβ may be useful in therapeutic treatments of dyslipidemia and regulating muscle growth. Rev-Erbβ is also a circadian regulated gene; its mRNA displays rhythmic expression in vivo and in serum-synchronized cell cultures. However, it is currently unknown to what extent Rev-Erbβ contributes to oscillations of the core circadian clock. However it has been shown that heme suppresses hepatic gluconeogenic gene expression and glucose output through the related Rev-Erbα receptor which mediates gene repression. Hence, the Rev-Erbα receptor detects heme and thereby coordinates the cellular clock, glucose homeostasis, and energy metabolism. Rev-Erbβ plays a role in skeletal muscle mitochondrial biogenesis. Originally Rev-Erbβ was thought to be functionally redundant of Rev-Erbα but recent findings prove that there are subtle differences. Rev-Erbβ ligands may be