Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood

Łukasz J. Sznajder (), Marina M. Scotti, Jihae Shin, Katarzyna Taylor, Franjo Ivankovic, Curtis A. Nutter, Faaiq N. Aslam, S. H. Subramony, Laura P. W. Ranum and Maurice S. Swanson ()
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Łukasz J. Sznajder: University of Florida, College of Medicine
Marina M. Scotti: University of Florida, College of Medicine
Jihae Shin: University of Florida, College of Medicine
Katarzyna Taylor: University of Florida, College of Medicine
Franjo Ivankovic: University of Florida, College of Medicine
Curtis A. Nutter: University of Florida, College of Medicine
Faaiq N. Aslam: University of Florida, College of Medicine
S. H. Subramony: University of Florida, College of Medicine
Laura P. W. Ranum: University of Florida, College of Medicine
Maurice S. Swanson: University of Florida, College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15962-x

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