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

Cellular & Molecular Immunology volume 20, pages 94–109 (2023)Cite this article

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Abstract

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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Acknowledgements

We thank Dr. Lionel Ivashkiv for providing human patient samples. This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP; No. 2020R1A2C1006101 and No. 2020M3A9B603885111 to SP) and by the Tow Foundation (to K-HP-M). Figure 1a was generated by BioRender.

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Author notes

  1. These authors contributed equally: Seyeon Bae, Kibyeong Kim.

Authors and Affiliations

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

    Seyeon Bae, Haemin Kim, Minjoon Lee, Brian Oh, Kaichi Kaneko & Kyung-Hyun Park-Min

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

    Seyeon Bae, Haemin Kim & Kyung-Hyun Park-Min

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

    Kibyeong Kim, Sungkook Ma & Sung Ho Park

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

    Kibyeong Kim & Jae Hoon Choi

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

    Keunsoo Kang

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

    Hojoong Kwak

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

    Eun Young Lee

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

    Kyung-Hyun Park-Min

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  1. Seyeon Bae
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Contributions

SB and KK designed and performed experiments and bioinformatics analysis, analyzed the data, and wrote the manuscript. KK performed the bioinformatics analysis and contributed his expertise. HK, ML, BO and KK performed experiments and analyzed data. HK, SM and JHC contributed their expertise. EYL, SHP and K-HP-M designed and supervised the study, and wrote the manuscript. K-HP-M conceptualized the study. All authors reviewed and provided input on the manuscript.

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Correspondence to Eun Young Lee, Sung Ho Park or Kyung-Hyun Park-Min.

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Bae, S., Kim, K., Kang, K. et al. RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts. Cell Mol Immunol 20, 94–109 (2023). https://doi.org/10.1038/s41423-022-00959-x

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