Histone Methyltransferase SETDB1 Maintains Brown Fat Cell Identity

Brown fat and beige fat can maintain the animal's body temperature under cold conditions with its special biological characteristics.It can also reduce fat cell enlargement and cell proliferation caused by metabolic dysfunction or excessive energy intake.In recent years,brown fat has received more and more attention from scientists.Some studies have shown that histone epigenetic modifications play an important role in the development and homeostasis of brown fat.For example,EHMT1 and HD AC 1/2 play an important role in maintaining the morphological structure and function of brown fat.SETDB1 as a histone methylation transferase can catalyze the trimethylation of H3K9.But there is currently no study on the development and maturation of SETDB1 in brown fat in the mice.We have great interest in this research.From previous cell experiments,it was found that SETDB1 maintains cell identity and the homeostasis of lipogenesis and lipolysis during adipocyte development.Therefore,mice using the Cre/LoxP recombination system were used to study the role of SETDB1 in the development and maintenance of mouse brown fat.Our results show that conditional knockout of SETDB1 in mice adipocytes can result in the normal survival.Knockout mice under normal temperature conditions can maintain normal body temperature and blood glucose levels compared to wild-type mice.However,the knockout mice had more food intake and drinking water than wild type mice.We found that the mice brown fat tends to like white fat in histology,whereas white fat itself is not much different.Further tests revealed that the cause of brown fat whitening was due to the overexpression of a large number of white fats and lipogenesis-related genes,resulting in an excessive increase of lipid droplets in the brown fat.So the brown fat tissue had the characteristics of white adipocytes.In vitro experiments also demonstrated that the loss of SETDB1 caused a change in cell identity.So this proves that was a cell autonomy changes.At the same time,RNAseq analysis found that gene expression in brown fats of knockout mice was most varied with respect to intracellular metabolism-related genes.Cold stimulation experiments in mice revealed that the ability of knockout mice to tolerate cold was greatly reduced.The body temperature of knockout mice under sudden cold stimulation was much lower than that of wild type mice.The above results demonstrate that SETDB1 is required for the maintenance of the cell identity and function homeostasis of mouse brown adipocytes.We are interested in how SETDB1 performs this function.Previously,it was reported that PPARa plays an important role in brown fat,and its expression is much higher than white fat.We detected a strong interaction between PPARa and SETDB1 through co-immunoprecipitation experiments.We speculated that PPARa may use the property of SETDB1 to suppress gene expression to control the expression of white fat-related genes in brown adipocytes timely and regulate the lipid droplets dynamic equilibrium in brown adipocytes.