RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts
- Authors
- Bae, Seyeon; Kim, Kibyeong; Kang, Keunsoo; Kim, Haemin; Lee, Minjoon; Oh, Brian; Kaneko, Kaichi; Ma, Sungkook; Choi, Jae Hoon; Kwak, Hojoong; Lee, Eun Young; Park, Sung Ho; Park-Min, Kyung-Hyun
- Issue Date
- Jan-2023
- Publisher
- Springer Nature
- Keywords
- enhancer RNAs; Osteoclasts; Rheumatoid arthritis; super-enhancers
- Citation
- Cellular and Molecular Immunology, v.20, no.1, pp.94 - 109
- Indexed
- SCIE
SCOPUS
- Journal Title
- Cellular and Molecular Immunology
- Volume
- 20
- Number
- 1
- Start Page
- 94
- End Page
- 109
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/182171
- DOI
- 10.1038/s41423-022-00959-x
- ISSN
- 1672-7681
- 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.
- Files in This Item
-
Go to Link
- Appears in
Collections - 서울 자연과학대학 > 서울 생명과학과 > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/182171)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.