Saturated Fat Impairs Circadian Transcriptomics through Histone Modification of Enhancers

Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. Cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. Overlap of mRNA and DNA regions associated with H3K27ac and pharmacological inhibition of histone acetyl transferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid-overload and redirects the circadian chromatin landscape leading to reprogramming of circadian genes in skeletal muscle. ### Competing Interest Statement The authors have declared no competing interest. * BMAL1 : also known as aryl hydrocarbon receptor nuclear translocator-like protein [ARNTL] CIART : Circadian Associated Repressor of Transcription CLOCK : Circadian Locomotor Output Cycles Kaput CRY : Cryptochrome DBP : D site of albumin promoter (albumin D-box) binding protein H3K27ac : Histone H3 Lysine 27 acetylation HPRT : hypoxanthine guanine phosphoribosyl transferase NR1D1 : Nuclear Receptor Subfamily 1 Group D Member 1, also known as REVERBα NR1D2 : Nuclear Receptor Subfamily 1 Group D Member 2, also known as REVERBβ PER : Period TBP : TATA box binding protein TEAD1 : Transcriptional enhancer factor TEF-1 18S : 18S ribosomal RNA