Misregulation of MiR-1 Processing is Associated with Heart Defects in Myotonic Dystrophy

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2011 Jun 21

PMID 21685920

Citations 163

Authors

Frederique Rau

Fernande Freyermuth

Charlotte Fugier

Jean-Philippe Villemin

Marie-Christine Fischer

Bernard Jost

Doulaye Dembele

Genevieve Gourdon

Annie Nicole

Denis Duboc

Karim Wahbi

John W Day

Harutoshi Fujimura

Masanori P Takahashi

Didier Auboeuf

Natacha Dreumont

Denis Furling

Nicolas Charlet-Berguerand

Affiliations

Soon will be listed here.

Abstract

Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium- and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.

Citing Articles

Functions of the Muscleblind-like protein family and their role in disease.

Zhou H, Xu J, Pan L Cell Commun Signal. 2025; 23(1):97.

PMID: 39966885 PMC: 11837677. DOI: 10.1186/s12964-025-02102-5.

MBNL splicing factors regulate the microtranscriptome of skeletal muscles.

Piasecka A, Szczesniak M, Sekrecki M, Kajdasz A, Sznajder L, Baud A Nucleic Acids Res. 2024; 52(19):12055-12073.

PMID: 39258536 PMC: 11514471. DOI: 10.1093/nar/gkae774.

The Muscleblind-like protein MBL-1 regulates microRNA expression in Caenorhabditis elegans through an evolutionarily conserved autoregulatory mechanism.

Verbeeren J, Teixeira J, Garcia S PLoS Genet. 2023; 19(12):e1011109.

PMID: 38134228 PMC: 10773944. DOI: 10.1371/journal.pgen.1011109.

RNA modification in cardiovascular disease: implications for therapeutic interventions.

Wang C, Hou X, Guan Q, Zhou H, Zhou L, Liu L Signal Transduct Target Ther. 2023; 8(1):412.

PMID: 37884527 PMC: 10603151. DOI: 10.1038/s41392-023-01638-7.

Cardiac involvement in patient-specific induced pluripotent stem cells of myotonic dystrophy type 1: unveiling the impact of voltage-gated sodium channels.

Pierre M, Djemai M, Chapotte-Baldacci C, Pouliot V, Puymirat J, Boutjdir M Front Physiol. 2023; 14:1258318.

PMID: 37791351 PMC: 10544896. DOI: 10.3389/fphys.2023.1258318.

References

Terentyev D, Belevych A, Terentyeva R, Martin M, Malana G, Kuhn D . miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res. 2009; 104(4):514-21. PMC: 4394868. DOI: 10.1161/CIRCRESAHA.108.181651. View

Wang G, Kearney D, De Biasi M, Taffet G, Cooper T . Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J Clin Invest. 2007; 117(10):2802-11. PMC: 1964514. DOI: 10.1172/JCI32308. View

Trabucchi M, Briata P, Garcia-Mayoral M, Haase A, Filipowicz W, Ramos A . The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature. 2009; 459(7249):1010-4. PMC: 2768332. DOI: 10.1038/nature08025. View

Heo I, Joo C, Cho J, Ha M, Han J, Kim V . Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008; 32(2):276-84. DOI: 10.1016/j.molcel.2008.09.014. View

Yi R, Qin Y, Macara I, Cullen B . Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003; 17(24):3011-6. PMC: 305252. DOI: 10.1101/gad.1158803. View

Hagan J, Piskounova E, Gregory R . Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol. 2009; 16(10):1021-5. PMC: 2758923. DOI: 10.1038/nsmb.1676. View

Savkur R, Philips A, Cooper T . Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001; 29(1):40-7. DOI: 10.1038/ng704. View

Yang W, Chendrimada T, Wang Q, Higuchi M, Seeburg P, Shiekhattar R . Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol. 2005; 13(1):13-21. PMC: 2950615. DOI: 10.1038/nsmb1041. View

Denli A, Tops B, Plasterk R, Ketting R, Hannon G . Processing of primary microRNAs by the Microprocessor complex. Nature. 2004; 432(7014):231-5. DOI: 10.1038/nature03049. View

10.

Guil S, Caceres J . The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat Struct Mol Biol. 2007; 14(7):591-6. DOI: 10.1038/nsmb1250. View

11.

Zhao Y, Ransom J, Li A, Vedantham V, von Drehle M, Muth A . Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129(2):303-17. DOI: 10.1016/j.cell.2007.03.030. View

12.

Rybak A, Fuchs H, Smirnova L, Brandt C, Pohl E, Nitsch R . A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol. 2008; 10(8):987-93. DOI: 10.1038/ncb1759. View

13.

Cacchiarelli D, Martone J, Girardi E, Cesana M, Incitti T, Morlando M . MicroRNAs involved in molecular circuitries relevant for the Duchenne muscular dystrophy pathogenesis are controlled by the dystrophin/nNOS pathway. Cell Metab. 2010; 12(4):341-351. DOI: 10.1016/j.cmet.2010.07.008. View

14.

Mankodi A, Takahashi M, Jiang H, Beck C, Bowers W, Moxley R . Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002; 10(1):35-44. DOI: 10.1016/s1097-2765(02)00563-4. View

15.

Mahadevan M, Yadava R, Yu Q, Balijepalli S, Frenzel-McCardell C, Bourne T . Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet. 2006; 38(9):1066-70. PMC: 2909745. DOI: 10.1038/ng1857. View

16.

Kuyumcu-Martinez N, Wang G, Cooper T . Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell. 2007; 28(1):68-78. PMC: 2083558. DOI: 10.1016/j.molcel.2007.07.027. View

17.

Phillips M, Harper P . Cardiac disease in myotonic dystrophy. Cardiovasc Res. 1997; 33(1):13-22. DOI: 10.1016/s0008-6363(96)00163-0. View

18.

Yan D, Dong X, Chen X, Wang L, Lu C, Wang J . MicroRNA-1/206 targets c-Met and inhibits rhabdomyosarcoma development. J Biol Chem. 2009; 284(43):29596-604. PMC: 2785592. DOI: 10.1074/jbc.M109.020511. View

19.

Ikeda S, He A, Kong S, Lu J, Bejar R, Bodyak N . MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Mol Cell Biol. 2009; 29(8):2193-204. PMC: 2663304. DOI: 10.1128/MCB.01222-08. View

20.

Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B . The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007; 13(4):486-91. DOI: 10.1038/nm1569. View