Yin Yang 1 (YY1) is a multifunctional transcription factor shown to be critical in a variety of biological processes. Although it is regulated by multiple types of post-translational modifications (PTMs)， whether YY1 is methylated， which enzyme methylates YY1， and hence the functional significance of YY1 methylation remains completely unknown. Here we reported the first methyltransferase， SET7/9 (KMT7)， capable of methylating YY1 at two highly conserved lysine (K) residues， K173 and K411， located in two distinct domains， one in the central glycine-rich region and the other in the very carboxyl-terminus. Functional studies revealed that SET7/9-mediated YY1 methylation regulated YY1 DNA-binding activity both in vitro and at specific genomic loci in cultured cells. Consistently， SET7/9-mediated YY1 methylation was shown to involve in YY1-regulated gene transcription and cell proliferation. Our findings revealed a novel regulatory strategy， methylation by lysine methyltransferase， imposed on YY1 protein， and linked YY1 methylation with its biological functions.