查看更多>>摘要：Monocyte/macrophage lineage cells are highly plastic and can differentiate into various cells under different environmental stimuli.Bone-resorbing osteoclasts are derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB ligand(RANKL).However,the epigenetic signature contributing to the fate commitment of monocyte/macrophage lineage differentiation into human osteoclasts is largely unknown.In this study,we identified RANKL-responsive human osteoclast-specific superenhancers(SEs)and SE-associated enhancer RNAs(SE-eRNAs)by integrating data obtained from ChIP-seq,ATAC-seq,nuclear RNA-seq and PRO-seq analyses.RANKL induced the formation of 200 SEs,which are large clusters of enhancers,while suppressing 148 SEs in macrophages.RANKL-responsive SEs were strongly correlated with genes in the osteoclastogenic program and were selectively increased in human osteoclasts but marginally presented in osteoblasts,CD4+T cells,and CD34+cells.In addition to the major transcription factors identified in osteoclasts,we found that BATF binding motifs were highly enriched in RANKL-responsive SEs.The depletion of BATF1/3 inhibited RANKL-induced osteoclast differentiation.Furthermore,we found increased chromatin accessibility in SE regions,where RNA polymerase II was significantly recruited to induce the extragenic transcription of SE-eRNAs,in human osteoclasts.Knocking down SE-eRNAs in the vicinity of the NFATc1 gene diminished the expression of NFATc1,a major regulator of osteoclasts,and osteoclast differentiation.Inhibiting BET proteins suppressed the formation of some RANKL-responsive SEs and NFATc1-associated SEs,and the expression of SE-eRNA:NFATc1.Moreover,SE-eRNA:NFATc1 was highly expressed in the synovial macrophages of rheumatoid arthritis patients exhibiting high-osteoclastogenic potential.Our genome-wide analysis revealed RANKL-inducible SEs and SE-eRNAs as osteoclast-specific signatures,which may contribute to the development of osteoclast-specific therapeutic interventions.
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