Funaguma Shunsuke, Iida Aritoshi, Saito Yoshihiko, Tanboon Jantima, De Los Reyes Francia Victoria, Sonehara Kyuto, Goto Yu-Ichi, Okada Yukinori, Hayashi Shinichiro, Nishino Ichizo
Department of Clinical Genome Analysis, Medical Genome Center (MGC), National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.
Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan.
Nat Commun. 2025 Feb 7;16(1):1318. doi: 10.1038/s41467-025-56567-6.
Transposon-like human element 1B (THE1B) originates from ancient retroviral sequences integrated into the primate genome approximately 50 million years ago, now accounting for at least 27,233 copies in the human genome, suggesting their extensive influence on human genomic architecture. Here we report identification of 19 THE1B fusion transcripts through short- and long-read RNA-seq analysis, 15 of which are previously unmapped, showing elevated expression in 16 individuals with sarcoid myopathy (SM), as compared to 400 controls with various other muscle diseases. Analysis of publicly available RNA-seq data indicated a correlation between the reduced expression of eight THE1B fusion transcripts and clinical improvement in individuals with cutaneous sarcoidosis receiving tofacitinib treatment. Single-cell or single-nucleus RNA-seq analyses of sarcoidosis not only confirmed these transcripts but also revealed a novel read-through transcript, SIRPB1-SIRPD, and TREM2.1, predominantly in granuloma-associated macrophages. The expression profiles of THE1B fusion transcripts in tuberculosis (TB) significantly differed from SM in single-cell RNA-seq data, suggesting that the differences between TB's caseous granulomas and sarcoidosis's non-caseous granulomas might be linked to disparate expression patterns of THE1B fusion transcripts. Our retrotrans-genomics approach has not only identified the genomic landscape of sarcoidosis but also provided new insights into its etiology.
转座子样人类元件1B（THE1B）起源于大约5000万年前整合到灵长类基因组中的古老逆转录病毒序列，目前在人类基因组中至少有27233个拷贝，表明它们对人类基因组结构有广泛影响。在此，我们报告通过短读长和长读长RNA测序分析鉴定出19种THE1B融合转录本，其中15种以前未被定位，与400名患有各种其他肌肉疾病的对照相比，它们在16名结节性肌病（SM）患者中表达升高。对公开可用的RNA测序数据的分析表明，8种THE1B融合转录本的表达降低与接受托法替布治疗的皮肤结节病患者的临床改善之间存在相关性。结节病的单细胞或单核RNA测序分析不仅证实了这些转录本，还揭示了一种新的通读转录本SIRPB1-SIRPD和TREM2.1，主要存在于肉芽肿相关巨噬细胞中。在单细胞RNA测序数据中，结核（TB）中THE1B融合转录本的表达谱与SM显著不同，这表明TB的干酪样肉芽肿和结节病的非干酪样肉芽肿之间的差异可能与THE1B融合转录本的不同表达模式有关。我们的逆转录基因组学方法不仅确定了结节病的基因组格局，还为其病因提供了新的见解。
