Mechanistic Action Of Histone Methyltransferase MLL4 In Skeletal Muscle Fiber Type Transition And Metabolism

With the rapid development of society,life style and dietary has been dramatically changed.Imbalance of calorie intake and consumption makes it difficult to maintain homeostasis of systemic metabolism.Accordingly,varied diseases related to this problem including obesity and type 2 diabetes mellitus are widespread,which becomes a heavy public burden to many countries.Notably,the common feature of metabolic diseases is the dysregulation of carbohydrate and lipid metabolism.Disorders of peripheral metabolic organs or their dysregulated fuel exchange affects the development of metabolic diseases.For example,reduced fatty acid oxidation of skeletal muscle and a decrease of lipid supply by liver for skeletal muscle are closely related to the development of metabolic diseases.There are numerous regulated mechanisms involving in maintaining metabolic homeostasis in response to varied stimuli,and transcriptional regulation as a basic regulated manner plays critical roles in mammalians.However,transcriptional regulation of skeletal muscle and liver metabolism are not fully understood.As the largest tissue,skeletal muscle is rich in mitochondria and has a strong capacity of fatty acid oxidation.It is composed of mature myofibers including type I fibers and type II fibers.The type I is oxidative fiber with preference on fatty acids utilization,whereas the type II is glycolytic fiber dependent on glucose consumption.Transformation of fiber type compositions largely affects muscle performance and metabolism upon physiological stimuli.Exactly how specific fiber type patterns are established and maintained remains unclear.The specific spatiotemporal transcriptional regulation of developmental genes is controlled by enhancers.The histone modification H3K4me1 is marked with enhancer activation,forming a "landing pad" for transcription factors occupancy and activating gene expression.Thus,enhancer activation is a key layer of regulation to adapt gene transcription to environment stimuli.Histone methyltransferases mixed-lineage leukemia 3/4(MLL3 / MLL4)within the COMPASS complex mainly account for modification of enhancer marker H3K4me1.MLL4,a dominant modifier,has been recognized as the major modifier of the enhancer marker H3K4me1.In this study,I found that long-term endurance exercise training induced the remodeling of human slow myofiber program and also increased the expression of MLL4.In addition,the protein level of MLL4 in slow muscle was higher than that in fast muscle.Further,I demonstrated that MLL4,a slow-twitch muscle enriched epigenetic modifier has been demonstrated to control type I fiber genes expression in vivo here.Mice lacking MLL4 specifically in skeletal muscle and primary myocyte resulted in a reduction of type I fibers with attenuated mitochondrial activity,which caused diminished fat utilization and endurance capacity during exercise.Mechanically,genome-wide Ch IP-seq and m RNA-seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2(MEF2)to activate transcription of slow-oxidative myofiber genes.Importantly,the MLL4/MEF2 regulatory circuit is associated with muscle fiber type remodeling in human disease.Thus,these data demonstrate MLL4 is a robust epigenetic modifier of skeletal muscle fiber type remodeling through cooperation with MEF2.These findings provide new insights into the epigenetic regulation of skeletal muscle function and new therapeutic opportunities for enhancing muscular fatty acid oxidation and endurance capacity to combat a variety of metabolic and muscular diseases.Besides fiber type switching,lipid metabolism of skeletal muscle is also regulated by fatty acids derived from other tissues.A new mechanism of liver lipids secretion has been demonstrated,which could be used for muscle fatty acid oxidation.Coat protein complex II(COPII),one of vesicular trafficking machinery transports endoplasmic reticulum(ER)cargoes to the Golgi apparatus,which is required for VLDL secretion from hepatocytes.However,in response to nutrient fluctuations,whether and how COPII is dynamically regulated remains unknown.By using in vitro live cell time-lapse imaging,I demonstrated that COPII-mediated secretion is regulated by nutrient stimuli.Further,forced expression of an active XBP1 s is sufficient to facilitate COPII-mediated secretion.Mechanically,by combination of Ch IP-seq and m RNA-seq approaches,it has been uncovered that dynamic binding of XBP1 s on COPII related gene promoters regulates their expression between fed and fasted liver.Moreover,liver specific knock out of IRE1? resulted in attenuated COPII-mediated Apo B secretion,leading to severe fatty liver and hypolipemia in fasted mice.Overexpression of XBP1 s in IRE1? knock out mice liver rescued COPII-mediated lipoprotein secretion,and reversed the fatty liver and hypolipidemia phenotypes.Therefore,these results revealed a new mechanism of liver VLDL secretion.The IRE1?-XBP1 s pathway functions as a nutrient-sensing regulatory nexus that couples nutrition demands and the COPII-mediated secretion of lipids to maintain systemic lipid homeostasis and liver derived lipid could be supplied for skeletal muscle utilization.Taken together,by using combination methods of genomic,genetic,bioinformatic and metabolic phenotyping,two researches regarding transcriptional regulation of skeletal muscle and liver metabolism have been conducted.It could effectively enhance lipid consumption by simultaneously targeting these two metabolic organs to combat metabolic diseases.Firstly,epigenetic modifier MLL4 has been identified to control muscle fiber type switch,lipid metabolism and endurance exercise.The underlying mechanism is that the MLL4/MEF2 axis orchestrates the type I muscle program,which is also operative in humans.Meantime,a new mechanism of liver lipids secretion that could be used for skeletal muscle fatty acid oxidation has also been demonstrated.The ER metabolic sensing IRE1?/XBP1 s signaling pathway in the liver couples COPII mediated hepatic lipoproteins secretion and nutrient availability.My studies regarding transcriptional regulation of skeletal muscle and liver metabolism provide a new potential intervention to combat a variety of metabolic diseases.