한빛사논문
- 조회543
Seyeon Bae # 1 2, Kibyeong Kim # 3 4, Keunsoo Kang 5, Haemin Kim 1 2, Minjoon Lee 1, Brian Oh 1, Kaichi Kaneko 1, Sungkook Ma 3, Jae Hoon Choi 4, Hojoong Kwak 6, Eun Young Lee 7, Sung Ho Park 8, Kyung-Hyun Park-Min 9 10 11
1Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 10021, USA.
2Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
3Department of Biological Science, Ulsan National Institute of Science & Technology (UNIST), Ulsan, 44919, Republic of Korea.
4Department of Life Science, College of Natural Sciences, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
5Department of Microbiology, Dankook University, Cheonan, 3116, Republic of Korea.
6Department of Molecular Biology and Genetics, Cornell University, Ithaca, USA.
7Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
8Department of Biological Science, Ulsan National Institute of Science & Technology (UNIST), Ulsan, 44919, Republic of Korea.
9Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 10021, USA.
10Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
11BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, 10021, USA.
#Contributed equally.
These authors contributed equally: Seyeon Bae, Kibyeong Kim
Corresponding Authors: Eun Young Lee, Sung Ho Park, Kyung-Hyun Park-Min
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.
논문정보
- Research article
- 2023년 01월 (BRIC 등록일 2023-01-04)
- 국내(교신)+국외 연구진
- 생명과학 > 면역학
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