首页|RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts

RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts

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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.

Osteoclastssuper-enhancersenhancer RNAsRheumatoid arthritis

Seyeon Bae、Kibyeong Kim、Keunsoo Kang、Haemin Kim、Minjoon Lee、Brian Oh、Kaichi Kaneko、Sungkook Ma、Jae Hoon Choi、Hojoong Kwak、Eun Young Lee、Sung Ho Park、Kyung-Hyun Park-Min

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Arthritis and Tissue Degeneration Program,David Z.Rosensweig Genomics Research Center,Hospital for Special Surgery,New York,NY 10021,USA

Department of Medicine,Weill Cornell Medical College,New York,NY 10065,USA

Department of Biological Science,Ulsan National Institute of Science&Technology(UNIST),Ulsan 44919,Republic of Korea

Department of Life Science,College of Natural Sciences,Research Institute for Natural Sciences,Hanyang University,Seoul,Korea

Department of Microbiology,Dankook University,Cheonan 3116,Republic of Korea

Department of Molecular Biology and Genetics,Cornell University,Ithaca,USA

Division of Rheumatology,Department of Internal Medicine,Seoul National University College of Medicine,Seoul,Korea

BCMB Allied Program,Weill Cornell Graduate School of Medical Sciences,New York,NY 10021,USA

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National Research Foundation of Korea(NRF)grants funded by the Korean governmentNational Research Foundation of Korea(NRF)grants funded by the Korean governmentNational Research Foundation of Korea(NRF)grants funded by the Korean governmentTow Foundation

MSIP2020R1A2C10061012020M3A9B603885111

2023

10.1038/s41423-022-00959-x

中国免疫学杂志(英文版)
中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI
影响因子：0.731
ISSN：1672-7681
年,卷(期)：2023.20(1)
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