Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers

Abstract

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.

TheDlk1-Dio3noncoding RNA cluster coordinately regulates mitochondrial respiration and chromatin structure to establish proper cell state for muscle differentiation

“…Metabolites generated by glucose and lipid metabolism are required for histone acetylation in myogenic cells (Das et al, 2017;Pillon et al, 2022;Yucel et al, 2019). Changes in histone modifications in skeletal myofibers have also been documented during exercise, which has wideranging effects on metabolic reactions and the production of metabolites (Egan andZierath, 2013, Hargreaves andSpriet, 2020;McGee et al, 2009).…”

“…At the genome level, myoblasts and myotubes express cell state-specific gene programs that form their distinct identities and are established by histone modification patterns that depend on availability of intermediate metabolites (Nguyen et al, 2019; Nieborak and Schneider, 2018). Metabolites generated by glucose and lipid metabolism are required for histone acetylation in myogenic cells (Das et al, 2017; Pillon et al, 2022; Yucel et al, 2019). Changes in histone modifications in skeletal myofibers have also been documented during exercise, which has wide-ranging effects on metabolic reactions and the production of metabolites (Egan and Zierath, 2013, Hargreaves and Spriet, 2020; McGee et al, 2009).…”