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. The 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. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases 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 may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle.
The authors are supported by grants from the Novo Nordisk Foundation (NNF14OC0011493 and NNF17OC0030088), EFSD/Novo Nordisk Foundation Future Leader Award (NNF21SA0072747), Swedish Diabetes Foundation (DIA2021-641 and DIA2021-645), Swedish Research Council (2015-00165 and 2018-02389), KID-funding (2-3591/2014), the Strategic Research Program in Diabetes at Karolinska Institutet (2009-1068), Marie Skłodowska-Curie Actions (European Commission, 675610 and 704978), and Novo Nordisk postdoctoral fellowship run in partnership with Karolinska Institutet. Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900).
Data Availability StatementData Availability
The raw and processed files for the RNA-seq and the ChIP-seq experiments have been deposited in the GEO repository under accession numbers GSE205424 and GSE205677.