Deaf1 and MeCP2 Interact to Coordinately Regulate 5-HT1A Receptor Gene Expression

Abstract

Deaf1 regulates 5-HT1A receptor gene (HTR1A) transcription by binding a 26-bp palindromic DNA sequence containing the rs6295 C(-1019) HTR1A polymorphism. However, Deaf1 cannot bind the G(-1019) HTR1A allele, which is associated with major depression. MeCP2 is impli-cated in serotonergic regulation and because the C(-1019) is a methylation site, I addressed whether MeCP2 alters Deaf1 regulation of HTR1A. MeCP2 and Deaf1 co-precipitated and bound the putative Deaf1 sites of the mouse HTR1A promoter in vivo. Binding of MeCP2 to the Deaf1 site was dependent on Deaf1 and MeCP2 increased Deaf1 recruitment to its site independ-ently of methylation. MeCP2, Deaf1 and their combination modulated transcription of human and mouse HTR1A luciferase reporter constructs, with Deaf1 having a dominant effect, Deaf1 actions were disrupted by mutation of the Deaf1 site(s). Deaf1 KO or MeCP2 cKO in mice in-creased functional 5-HT1A autoreceptor-mediated hypothermia response. Overall, MeCP2 and Deaf1 coordinately regulate the HTR1A promoter.