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Introduction Muscle fitness is a key determinant of human health and disease. Muscle performance and fatigability are determined by the structural and metabolic properties of the specialized myofibers (1-3). Myofibers [...], Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-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, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.

Introduction Fatty acids serve both as a crucial metabolic fuel and as a core structure component of cell membranes to support life. Fatty acid synthase (Fasn) deficiency results in embryonic [...], De novo lipogenesis is tightly regulated by insulin and nutritional signals to maintain metabolic homeostasis. Excessive lipogenesis induces lipotoxicity, leading to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Genetic lipogenic programs have been extensively investigated, but epigenetic regulation of lipogenesis is poorly understood. Here, we identified Slug as an important epigenetic regulator of lipogenesis. Hepatic Slug levels were markedly upregulated in mice by either feeding or insulin treatment. In primary hepatocytes, insulin stimulation increased Slug expression, stability, and interactions with epigenetic enzyme lysine-specific demethylase-1 (Lsd1). Slug bound to the fatty acid synthase (Fasn) promoter where Slug-associated Lsd1 catalyzed H3K9 demethylation, thereby stimulating Fasn expression and lipogenesis. Ablation of Slug blunted insulin-stimulated lipogenesis. Conversely, overexpression of Slug, but not a Lsd1 binding-defective Slug mutant, stimulated Fasn expression and lipogenesis. Lsd1 inhibitor treatment also blocked Slug-stimulated lipogenesis. Remarkably, hepatocyte-specific deletion of Slug inhibited the hepatic lipogenic program and protected against obesity-associated NAFLD, insulin resistance, and glucose intolerance in mice. Conversely, liver- restricted overexpression of Slug, but not the Lsd1 binding-defective Slug mutant, had the opposite effects. These results unveil an insulin/Slug/Lsd1/H3K9 demethylation lipogenic pathway that promotes NAFLD and type 2 diabetes.

Gene duplication is thought to facilitate increasing complexity in the evolution of life. The fate of most duplicated genes is nonfunctionalization: functional decay resulting from the accumulation of mutations. According [...]

Introduction The members of the family of intracellular lipid-binding proteins (iLBP) are known to play vital roles in the transport of hydrophobic ligands such as long-chain fatty acids and retinoid [...], The fatty acid-binding protein (fabp) genes belong to the multigene family of intracellular lipid-binding proteins. To date, 12 different FABPs have been identified in vertebrate genomes. Owing to the teleost-specific genome duplication event, many fishes have duplicated copies of the fabp genes. Here, we identified and characterized the fabp genes of spotted green pufferfish (Tetraodon nigroviridis). Seven fabp genes were identified, out of which, two were retained in the pufferfish genome as duplicated copies. Each putative pufferfish Fabp protein shares greatest sequence identity and similarity with their teleost and tetrapod orthologs, and clustered together as a distinct clade in phylogenetic analysis. Conserved gene synteny was evident between the pufferfish fabp genes and the orthologs of human, zebrafish, three-spined stickleback, and medaka FABP/fabp genes, providing evidence that the duplicated copies of pufferfish fabp genes most likely arose as a result of the teleost- specific genome duplication event. The differential tissue-specific distribution of pufferfish fabp transcripts suggests divergent spatial regulation of duplicated pairs of fabp genes. Key words: spotted green pufferfish, fatty acid-binding protein, teleost-specific genome duplication. Les genes codant pour des proteines de liaison aux acides gras (fabp) appartiennent a une famille multigenique de proteines intracellulaires de liaison des lipides. A ce jour, 12 FABP differents ont ete identifies au sein des genomes de vertebres. En raison de l'evenement de duplication genomique specifique des teleosteens, plusieurs poissons ont des copies dupliquees des genes fabp. Dans ce travail, les auteurs identifient et caracterisent les genes fabp chez le tetraodon vert (Tetraodon nigroviridis). Sept genes fapb ont ete identifies, dont deux representent des copies dupliquees qui ont ete conservees au sein du genome du tetraodon. Chaque proteine Fabp putative chez le tetraodon presente une identite et une similarite maximale avec son orthologue chez les teleosteens et les tetrapodes, de maniere a former un clade distinct en analyse phylogenetique. Une syntenie genique etait evidente entre les genes fabp du tetraodon et leurs orthologues chez l'humain, le poisson zebre, l'epinoche a trois epines et le medaka, ce qui suggere que les copies dupliquees des genes FABP/fabp chez le tetraodon sont vraisemblablement le resultat de l'evenement de duplication genomique specifique des teleosteens. La distribution tissus-specifique differentielle des transcrits fabp suggere une regulation spatiale divergente des paires de genes fabp dupliques. [Traduit par la Redaction] Mots-cles: tetraodon vert, proteine de liaison des acides gras, duplication genomique specifique des teleosteens.