Pathological Effects Of Histone Methyltransferase G9a In Various Tissues

G9a,encoded by Ehmt2,is an important histone methyltransferase with a classical SET domain,and is responsible for H3K9me1 and H3K9me2 on euchromatin.G9a plays critical roles on gene transcription not only by its methyltransferase activity,but also by recruiting transcriptional regulators through its scaffold role.Previous reports have demonstrated that G9a is involved in the development and progression of a variety of diseases,such as tumor,embryonic developmental disease,neurological diseases and immune diseases.Whole body G9a-deficient mice are early embryonic lethal,thus,in order to further understand the function of G9a in different tissues,liver-,or pancreas-,or kidney-specific knockout G9a mice were created,and specific role of G9a in these tissues were investigated under different stimuli.To investigate the role of G9a in the progression of NASH（Nonalcoholic steatohepatitis）,MCD（Methionine choline deficient）diet was used to treat the wild-type（WT）mice and liver-specific G9a knockout(Ehmt2^AlbKO)mice.After two weeks of MCD diet feeding,there was no difference in liver injury between these two mouse groups.However,after 4 weeks of MCD diet feeding,increased serum ALT level,aggravated hepatic steatosis and ER stress were found in the Ehmt2^AlbKO mice,suggesting a more severe liver injury in Ehmt2^AlbKO mice compared to the WT mice.Further experiments showed that G9a repressed the expression of Chop,one of key factors of ER stress,in vivo and in vitro.To reveal the function of G9a onβcell,HFD was used to treat the WT mice andβcell-specific G9a knockout(Ehmt2^Ins2KO)mice.After 28 weeks of HFD feeding,WT mice developed hyperglycemia and insulin resistance.However,there were no significant difference in the levels of blood glucose and insulin resistance in WT and Ehmt2^Ins2KO mice.In order to study the function of G9a in kidney,Pax2-Cre mice were crossed with Ehmt2^loxp/loxp mice.However,homozygous and few heterozygous Ehmt2^Pax2mice were lethal at P21.Further research demonstrated that homozygous and heterozygous Ehmt2^Pax2mice were died after E13.5.In summary,our results indicated G9a plays essential roles in NASH and early kidney development,however,mechanical studies are still lacking.