Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL, 32610, USA.
Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School and Rutgers Cancer Institute of New Jersey, Newark, NJ, 07103, USA.
Nat Commun. 2020 Apr 24;11(1):2022. doi: 10.1038/s41467-020-15962-x.
The thymus is a primary lymphoid organ that plays an essential role in T lymphocyte maturation and selection during development of one arm of the mammalian adaptive immune response. Although transcriptional mechanisms have been well documented in thymocyte development, co-/post-transcriptional modifications are also important but have received less attention. Here we demonstrate that the RNA alternative splicing factor MBNL1, which is sequestered in nuclear RNA foci by C(C)UG microsatellite expansions in myotonic dystrophy (DM), is essential for normal thymus development and function. Mbnl1 129S1 knockout mice develop postnatal thymic hyperplasia with thymocyte accumulation. Transcriptome analysis indicates numerous gene expression and RNA mis-splicing events, including transcription factors from the TCF/LEF family. CNBP, the gene containing an intronic CCTG microsatellite expansion in DM type 2 (DM2), is coordinately expressed with MBNL1 in the developing thymus and DM2 CCTG expansions induce similar transcriptome alterations in DM2 blood, which thus serve as disease-specific biomarkers.
胸腺是初级淋巴器官，在哺乳动物适应性免疫反应的一个分支的发育过程中，对于 T 淋巴细胞的成熟和选择起着至关重要的作用。尽管在胸腺细胞发育过程中已经很好地记录了转录机制，但共/后转录修饰也很重要，但受到的关注较少。在这里，我们证明了 RNA 可变剪接因子 MBNL1 在肌萎缩性侧索硬化症 (DM) 中由于 C(C)UG 微卫星扩展而被隔离在核 RNA 焦点中，对于正常的胸腺发育和功能是必不可少的。Mbnl1 129S1 敲除小鼠在出生后会出现胸腺增生，伴有胸腺细胞积累。转录组分析表明存在许多基因表达和 RNA 错误剪接事件，包括 TCF/LEF 家族的转录因子。CNBP 是 DM2 中包含内含子 CCTG 微卫星扩展的基因，与 MBNL1 在发育中的胸腺中协调表达，并且 DM2 CCTG 扩展在 DM2 血液中诱导类似的转录组改变，因此可作为疾病特异性生物标志物。
