RbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

Chantal Sellier; Estefanía Cerro-Herreros; Markus Blatter; Fernande Freyermuth; Angeline Gaucherot; Frank Ruffenach; Partha Sarkar; Jack Puymirat; Bjarne Udd; John W. Day; Giovanni Meola; Guillaume Bassez; Harutoshi Fujimura; Masanori P. Takahashi; Benedikt Schoser; Denis Furling; Ruben Artero; Frédéric H.T. Allain; Beatriz Llamusi; Nicolas Charlet-Berguerand

doi:10.1038/s41467-018-04370-x

RbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

Chantal Sellier, Estefanía Cerro-Herreros, Markus Blatter, Fernande Freyermuth, Angeline Gaucherot, Frank Ruffenach, Partha Sarkar, Jack Puymirat, Bjarne Udd, John W. Day, Giovanni Meola, Guillaume Bassez, Harutoshi Fujimura, Masanori P. Takahashi, Benedikt Schoser, Denis Furling, Ruben Artero, Frédéric H.T. Allain, Beatriz Llamusi, Nicolas Charlet-Berguerand

Neurology

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.

Original language	English (US)
Article number	2009
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04370-x
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Sellier, C., Cerro-Herreros, E., Blatter, M., Freyermuth, F., Gaucherot, A., Ruffenach, F., Sarkar, P., Puymirat, J., Udd, B., Day, J. W., Meola, G., Bassez, G., Fujimura, H., Takahashi, M. P., Schoser, B., Furling, D., Artero, R., Allain, F. H. T., Llamusi, B., & Charlet-Berguerand, N. (2018). RbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nature communications, 9(1), Article 2009. https://doi.org/10.1038/s41467-018-04370-x

Sellier, C, Cerro-Herreros, E, Blatter, M, Freyermuth, F, Gaucherot, A, Ruffenach, F, Sarkar, P, Puymirat, J, Udd, B, Day, JW, Meola, G, Bassez, G, Fujimura, H, Takahashi, MP, Schoser, B, Furling, D, Artero, R, Allain, FHT, Llamusi, B & Charlet-Berguerand, N 2018, 'RbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences', Nature communications, vol. 9, no. 1, 2009. https://doi.org/10.1038/s41467-018-04370-x

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title = "RbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences",

abstract = "Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.",

author = "Chantal Sellier and Estefan{\'i}a Cerro-Herreros and Markus Blatter and Fernande Freyermuth and Angeline Gaucherot and Frank Ruffenach and Partha Sarkar and Jack Puymirat and Bjarne Udd and Day, {John W.} and Giovanni Meola and Guillaume Bassez and Harutoshi Fujimura and Takahashi, {Masanori P.} and Benedikt Schoser and Denis Furling and Ruben Artero and Allain, {Fr{\'e}d{\'e}ric H.T.} and Beatriz Llamusi and Nicolas Charlet-Berguerand",

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AU - Sellier, Chantal

AU - Cerro-Herreros, Estefanía

AU - Blatter, Markus

AU - Freyermuth, Fernande

AU - Gaucherot, Angeline

AU - Ruffenach, Frank

AU - Sarkar, Partha

AU - Puymirat, Jack

AU - Udd, Bjarne

AU - Day, John W.

AU - Meola, Giovanni

AU - Bassez, Guillaume

AU - Fujimura, Harutoshi

AU - Takahashi, Masanori P.

AU - Schoser, Benedikt

AU - Furling, Denis

AU - Artero, Ruben

AU - Allain, Frédéric H.T.

AU - Llamusi, Beatriz

AU - Charlet-Berguerand, Nicolas

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.

AB - Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.

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RbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

Abstract

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