E2F1 methylation by SETD6 regulates SETD6 expression via positive feedback mechanism

Abstract The protein lysine methyltransferase SETD6 has been shown to influence different cellular activities and are critically involved in the regulation of diverse developmental and pathological processes. However, the upstream signal which regulates the mRNA expression of SETD6 is not known. Bioinformatics analysis revealed that SETD6 promoter has a binding site for the transcription factor E2F1. Using various experimental systems, we confirmed that E2F1 binds to the SETD6 promoter and regulates SETD6 mRNA expression. Our further observation that this phenomenon is SETD6 dependent, suggested that SETD6 and E2F1 are linked. We next demonstrate that SETD6 mono-methylates E2F1 specifically at K117 in-vitro and in cells. Finally, we show that E2F1 methylation at K117 positively regulates the expression level of SETD6 mRNA. Depletion of SETD6 or overexpression of E2F1 K117R mutant which canot be methylated by SETD6, reverses the effect. Taken together, our data provide evidence for a positive feedback mechanism which regulates the expression of SETD6 by E2F1 in a SETD6 methylation dependent manner and highlight the importance of protein lysine methyltransferases and lysine methylation signaling in the regulation of gene transcription.