Integration of circadian and hypoxia signaling via non‐canonical heterodimerization

CLOCK, BMAL1, and HIFs are basic helix-loop-helix and Per-Arnt-Sim domain (bHLH-PAS) proteins, which function as transcription factors. bHLH-PAS proteins are designated in two classes. Many class I proteins are regulated by environmental signals via their PAS domains, but such signals have not been identified for all. Class II (ARNTs and BMALs) are partners for Class I and can be regulated by synthetic PAS ligands. Previous studies suggested restricted dimerization for bHLH-PAS proteins. BMAL1 and BMAL2 were believed to dimerize only with CLOCK and NPAS2, while ARNT was thought to dimerize with most Class I proteins except for CLOCK and NPAS2. The logic underlying these assumptions was flawed, and evidence supports dimerization of both HIF1α and HIF2α with BMAL1.