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

Cellular & Molecular Immunology 2023年第1期20卷 94-109页

作者： 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 Arthritis and Tissue Degeneration Program David Z.Rosensweig Genomics Research CenterHospital for Special SurgeryNew YorkNY10021USA Department of Medicine Weill Cornell Medical CollegeNew YorkNY10065USA Department of Biological Science Ulsan National Institute of Science&Technology(UNIST)Ulsan44919Republic of Korea Department of Life Science College of Natural SciencesResearch Institute for Natural SciencesHanyang UniversitySeoulKorea Department of Microbiology Dankook UniversityCheonan3116Republic of Korea Department of Molecular Biology and Genetics Cornell UniversityIthacaUSA Division of Rheumatology Department of Internal MedicineSeoul National University College of MedicineSeoulKorea BCMB Allied Program Weill Cornell Graduate School of Medical SciencesNew YorkNY10021USA

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 t

关键词： Osteoclasts super-enhancers enhancer RNAs Rheumatoid arthritis

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Enhancer RNAs: A missing regulatory layer in gene transcription

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Science China(Life Sciences) 2019年第7期62卷 905-912页

作者： Renfang Mao Yuanyuan Wu Yue Ming Yuanpei Xu Shouyan Wang Xia Chen Xiaoying Wang Yihui Fan Department of Pathophysiology School of MedicineNantong UniversityNantong 226019China Basic Medical Research Center School of MedicineNantong UniversityNantong 226019China Department of Immunology School of MedicineNantong UniversityNantong 226019China

enhancers and super-enhancers exert indispensable roles in maintaining cell identity through spatiotemporally regulating gene ***,active enhancers and super-enhancers also produce transcripts termed enhancer RNAs(eRNAs) from their DNA *** enhancers have been identified for more than 30 years,widespread transcription from enhancers are just discovered by genome-wide sequencing and considered as the key to understand longstanding questions in gene ***-transcribed enhancers are marked by histone modifications such as H3K4m1/2 and H3K27Ac,and enriched with transcription regulatory factors such as LDTFs,P300,CBP,BRD4 and *** regulatory factors might constitute a Mega-Trans-like complex to potently activate *** to mRNAs,eRNAs are quite unstable and play roles at ***,it has been shown that e RNAs promote formation of enhancer-promoter *** studies also demonstrated that eRNAs help the binding of RNA polymerase II(RNAPII) or transition of paused RNAPII by de-association of the negative elongation factor(NELF) ***,these proposed mechanisms are not universally accepted and still under ***,we comprehensively summarize the reported findings and make perspectives for future *** also believe that super-enhancer derived RNAs(seRNAs) might be informative to understand the nature of super-enhancers.

关键词： enhancer RNAs (eRNAs) enhancers super-enhancers super-enhancer RNAs (seRNAs) gene transcription

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