Identification of an intronic enhancer regulating RANKL expression in osteocytic cells.

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Minglu Yan, Masayuki Tsukasaki, Ryunosuke Muro, Yutaro Ando, Kazutaka Nakamura, Noriko Komatsu, Takeshi Nitta, Tadashi Okamura, Kazuo Okamoto, Hiroshi Takayanagi
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Abstract

The bony skeleton is continuously renewed throughout adult life by the bone remodeling process, in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms. Osteocytes regulate bone remodeling by producing the osteoclast differentiation factor RANKL (encoded by the TNFSF11 gene). However, the precise mechanisms underlying RANKL expression in osteocytes are still elusive. Here, we explored the epigenomic landscape of osteocytic cells and identified a hitherto-undescribed osteocytic cell-specific intronic enhancer in the TNFSF11 gene locus. Bioinformatics analyses showed that transcription factors involved in cell death and senescence act on this intronic enhancer region. Single-cell transcriptomic data analysis demonstrated that cell death signaling increased RANKL expression in osteocytic cells. Genetic deletion of the intronic enhancer led to a high-bone-mass phenotype with decreased levels of RANKL in osteocytic cells and osteoclastogenesis in the adult stage, while RANKL expression was not affected in osteoblasts or lymphocytes. These data suggest that osteocytes may utilize a specialized regulatory element to facilitate osteoclast formation at the bone surface to be resorbed by linking signals from cellular senescence/death and RANKL expression.

Abstract Image

骨细胞中调控RANKL表达的内含子增强子的鉴定。
在整个成人生活中,骨骼通过骨重塑过程不断更新,在这个过程中,破骨细胞通过很大程度上未知的机制去除旧的或受损的骨。骨细胞通过产生破骨细胞分化因子RANKL(由TNFSF11基因编码)调节骨重塑。然而,RANKL在骨细胞中表达的确切机制尚不清楚。在这里,我们探索了骨细胞的表观基因组景观,并在TNFSF11基因位点发现了迄今未描述的骨细胞特异性内含子增强子。生物信息学分析表明,参与细胞死亡和衰老的转录因子作用于该内含子增强子区域。单细胞转录组数据分析表明,细胞死亡信号增加了骨细胞中RANKL的表达。内含子增强子的基因缺失导致成人期成骨细胞和破骨细胞生成中RANKL水平下降的高骨量表型,而成骨细胞或淋巴细胞中的RANKL表达不受影响。这些数据表明,骨细胞可能利用一种特殊的调控元件,通过连接细胞衰老/死亡和RANKL表达的信号,促进骨表面破骨细胞的形成并被吸收。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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