We have identified an indel in the stress response promoter motif that alters DNA–protein complexes formed by Nrf2, a transcriptional activator. This indel is an excellent candidate contributing to strain differences in Per3 expression and is also likely a molecular locus regulating interaction between stress and alcohol responses. The indel in the STRE promoter element is an especially strong candidate for the cis-QTL. EMSA showed two DNA–protein complexes that were unique to the D allele promoter variant associated with higher gene expression. In contrast, low expression of Per3 is linked to the B allele promoter variant. Interestingly, STREs modulate transcription of stress-responsive genes under various cellular challenges, including oxidative stress.49, 51 Because alcohol is known to induce oxidative stress in the brain,52, 53 the STRE variant may be an important regulator of basal and alcohol/stress-responsive expression of Per3.
