Dual role for the methyltransferase G9a in the maintenance of β-globin gene transcription in adult erythroid cells

Abstract

Using a proteomics screen, we have identified the methyltransferase G9a as an interacting partner of the hematopoietic activator NF-E2. We show that G9a is recruited to the β-globin locus in a NF-E2-dependent manner and spreads over the entire locus. While G9a is often regarded as a corepressor, knocking down this protein in differentiating adult erythroid cells leads to repression of the adult β^maj globin gene and aberrant reactivation of the embryonic β-like globin gene E^y. While in adult cells G9a maintains E^y in a repressed state via dimethylation of histone H3 at lysines 9 and 27, it activates β^maj transcription in a methyltransferase-independent manner. Interestingly, the demethylase UTX is recruited to the β^maj (but not the E^y) promoter where it antagonizes G9a-dependent H3K27 dimethylation. Collectively, these results reveal a dual role for G9a in maintaining proper expression (both repression and activation) of the β-globin genes in differentiating adult erythroid cells.