Histone deacetylase HDA-5 regulates lipid metabolism through H4K5 and H4K8 acetylation in Caenorhabditis elegans

Obesity, a widely recognized pathological factor contributing to the onset of metabolic diseases, has been strongly linked to epigenetic modifications. It is ambiguous how histone modifications, especially histone acetylation, are involved in lipid metabolism. By analyzing existing transcriptome data of Caenorhabditis elegans glp-1(e2141ts) mutants, we found that the expression of six genes encoding histone deacetylases was significantly up-regulated, which was accompanied by a reduction in the histone H4 acetylation at Lysine 5, 8, 12, and 16 in the germline-deficient worms. Of these histone deacetylases, HDA-4, HDA-5, and SIR-2.2 were involved in reduced histone H4 acetylation modifications in glp-1(e2141ts) mutants. Interestingly, lipid accumulation occurred after knockdown of the three deacetylase genes by RNAi, suggesting that low levels of H4 acetylation are required to maintain lipid homeostasis in glp-1(e2141ts) mutants. In wild-type worms, only knockdown of hda-5 by RNAi led to an increase in both lipid contents and histone modification of H4K5ac and H4K8ac. Integrated analysis of ChIP-seq and RNA-seq data revealed that knockdown of hda-5 by RNAi up-regulated the expression of fatty acid desaturase genes fat-2, fat-4, fat-5, and ttm-5 in H4K5ac and H4K8ac-dependent manners. Upregulation of these genes contributed to lipid accumulation in hda-5 (RNAi) worms. This study elucidates the underlying mechanism by which H4K5ac and H4K8ac modifications regulate lipid homeostasis in C. elegans.