Cells generate a vast repertoire of lipid molecules whose functions are poorly understood. To investigate whether lipids can regulate cell fate decisions, we carried out a systematic lipidomic analysis and perturbation of lipid metabolism in cultured human epidermal keratinocytes, determining associations with the onset of differentiation. We identified individual lipid species that induced exit from the epidermal stem cell compartment. Our observations suggest that more research is warranted on the regulation of biological processes via lipid species, moving beyond the more conventional contribution of proteins and nucleic acids.
While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. A lipidomic analysis of primary human keratinocytes revealed accumulation of numerous lipid species during suspension-induced differentiation. A small interfering RNA screen of 258 lipid-modifying enzymes identified two genes that on knockdown induced epidermal differentiation: ELOVL1, encoding elongation of very long-chain fatty acids protein 1, and SLC27A1, encoding fatty acid transport protein 1. By intersecting lipidomic datasets from suspension-induced differentiation and knockdown keratinocytes, we pinpointed candidate bioactive lipid subspecies as differentiation regulators. Several of these—ceramides and glucosylceramides—induced differentiation when added to primary keratinocytes in culture. Our results reveal the potential of lipid subspecies to regulate exit from the epidermal stem cell compartment.