Characterization of Mice with Liver‐Specific Knockout of Histone Methyltransferase G9a

Abstract

G9a is an epigenetic enzyme essential for a key gene silencing mark, histone H3 dimethylation at lysine‐9 (H3K9me2). G9a is important for embryonic development and differentiation of multiple tissues. However, little is known about the role of G9a in liver. To understand the role of G9a in regulating hepatic gene expression and pathophysiology, we generated mice with liver‐specific knockout (Liv‐KO) of G9a by crossing G9a floxed mice with Alb‐cre mice. G9a Liv‐KO mice had marked loss of G9a and H3K9me2 proteins in liver. Unstressed adult male G9a Liv‐KO mice had no overt liver injury or infiltration of inflammatory cells. However, G9a Liv‐KO mice had higher blood levels of total cholesterol; results of hepatic gene expression suggest that the underlying mechanism may be increased biosynthesis but decreased catabolism of cholesterol. Consistent with a key role of G9a in gene silencing, G9a Liv‐KO mice had dramatic ectopic induction of certain genes normally expressed in neural and immune systems. Additionally, G9a Liv‐KO mice had hepatic down‐regulation of many cytoprotective genes and certain important drug‐processing genes, elevated endogenous reactive oxygen species, but lower glutathione and nuclear Nrf2, a master regulator of cytoprotection. Sixteen hours after LPS treatment, G9a Liv‐KO mice had aggravated lipid peroxidation and proinflammatory response, manifested by much higher hepatic induction of IP‐10, Mcp‐1, Icam‐1, and iNos, as well as proinflammatory transcription factors c‐Jun, Stat1, Irf‐1, and Atf4. Thus, G9a plays a key role in regulating hepatic gene expression by silencing neural and proinflammatory genes but maintaining/activating cytoprotective genes, by which G9a may protect the liver from injuries induced by various environmental stressors.