A Role for Widely Interspaced Zinc Finger (WIZ) in Retention of the G9a Methyltransferase on Chromatin

G9a and GLP lysine methyltransferases form a heterodimeric complex that is responsible for the majority of histone H3 lysine 9 mono- and di-methylation (H3K9me1/me2). Widely interspaced zinc finger (WIZ) associates with the G9a-GLP protein complex, but its role in mediating lysine methylation is poorly defined. Here, we show that WIZ regulates global H3K9me2 levels by facilitating the interaction of G9a with chromatin. Disrupting the association of G9a-GLP with chromatin by depleting WIZ resulted in altered gene expression and protein-protein interactions that were distinguishable from that of small molecule-based inhibition of G9a/GLP, supporting discrete functions of the G9a-GLP-WIZ chromatin complex in addition to H3K9me2 methylation. Background: G9a-GLP lysine methyltransferases mono- and di-methylate histone H3 lysine 9 (H3K9me2). Results: Widely interspaced zinc finger (WIZ) regulates H3K9me2 levels through a mechanism that involves retention of G9a on chromatin. Conclusion: The G9a-GLP-WIZ complex has unique functions when bound to chromatin that are independent of the H3K9me2 mark. Significance: Combining pharmacologic and genetic manipulations is essential to any translational hypotheses related to G9a function.