Study The Function Of UHRF Protein Family By Liver Specific Overexpression Mouse Model

The mammalian UHRF family proteins,including UHRF1 and UHRF2,play important roles in epigenetics,cell cycle regulation and tumor development.Although UHRF1 and UHRF2 are highly similar in structure and possess overlapped function,they are not functionally redundant.In this study,we used Cre-Loxp system to construct mouse models of liver specific overexpression of human UHRF1/2 in C57BL/6 genetic background to further explore the function of UHRF family proteins.The mice with liver specific overexpression of UHRF1 or UHRF2(UHRF1/2^{hep OE})were able to grow and reproduce normally with normal basic morphology.HE staining showed that the liver size and morphology of UHRF1/2^{hep OE} mice were normal.The results of mass spectrometry showed that there was no difference in DNA methylation and hydroxymethylation level between UHRF2^{hep OE} mice and wild-type mice.Western Blot and IHC showed that overexpression of UHRF2 did not affect the process of liver regeneration.Furthermore,glucose and fatty acid metabolisms were normal for UHRF2^{hep OE} mice.Interestingly,we found that UHRF1 was involved in the regulation of liver metabolism in mice.Comapred to the control mice,there was an increased level of blood glucose in UHRF1^{hep OE} mice under the condition of eating and fasting.Oil red O staining experiment showed an accumulation of large number of lipid droplets in the liver tissues of UHRF1^{hep OE} mice.Glucose tolerance experiment and insulin tolerance experiment showed reduced glucose tolerance and insulin sensitivity for UHRF1^hep OEep OE mice.All these phenotypes were not observed in UHRF2^{hep OE} mice.RT-PCR analysis showed that overexpression of UHRF1 in the liver resulted in the up-regulation of genes related to gluconeogenesis,glycogen synthesis,and triglyceride synthesis.These results reveal for the first time a role of UHRF1 in the regulation of liver metabolism,although the specific molecular mechanism remains to be studied.