LncRNA lncLy6C induced by microbiota metabolite butyrate promotes differentiation of Ly6Chigh to Ly6Cint/neg macrophages through lncLy6C/C/EBPβ/Nr4A1 axis

Macrophages are mainly divided into two populations, which play a different role in physiological and pathological conditions. The differentiation of these cells may be regulated by transcription factors. However, it is unclear how to modulate these transcription factors to affect differentiation of these cells. Here, we found that lncLy6C, a novel ultraconserved lncRNA, promotes differentiation of Ly6C(high) inflammatory monocytes into Ly6C(low/neg) resident macrophages. We demonstrate that gut microbiota metabolites butyrate upregulates the expression of lncLy6C. LncLy6C deficient mice had markedly increased Ly6C(high) pro-inflammatory monocytes and reduced Ly6C(neg) resident macrophages. LncLy6C not only bound with transcription factor C/EBP beta but also bound with multiple lysine methyltransferases of H3K4me3 to specifically promote the enrichment of C/EBP beta and H3K4me3 marks on the promoter region of Nr4A1, which can promote Ly6C(high) into Ly6C(neg) macrophages. As a result, lncLy6C causes the upregulation of Nr4A1 to promote Ly6C(high) inflammatory monocytes to differentiate into Ly6C(int/neg) resident macrophages.