Academic Journal
RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts
| العنوان: | RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts |
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| المؤلفون: | 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 |
| بيانات النشر: | CHIN SOCIETY IMMUNOLOGY |
| سنة النشر: | 2023 |
| المجموعة: | ScholarWorks@UNIST (Ulsan National Institute of Science and Technology) |
| الوصف: | 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-kappa B 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 1672-7681 |
| Relation: | CELLULAR & MOLECULAR IMMUNOLOGY, v.20, pp.94 - 109; https://scholarworks.unist.ac.kr/handle/201301/61333; 42220; 2-s2.0-85143885819; 000898603500001 |
| DOI: | 10.1038/s41423-022-00959-x |
| الاتاحة: | https://scholarworks.unist.ac.kr/handle/201301/61333 https://doi.org/10.1038/s41423-022-00959-x |
| رقم الانضمام: | edsbas.FA33D1E0 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 16727681 |
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| DOI: | 10.1038/s41423-022-00959-x |