RNA steady-state defects in myotonic dystrophy are linked to nuclear exclusion of SHARP

• Published in: EMBO reports Vol. 12; no. 7; pp. 735 - 742
• Main Authors: Dansithong, Warunee, Jog, Sonali P, Paul, Sharan, Mohammadzadeh, Robabeh, Tring, Stephanie, Kwok, Yukwah, Fry, Rebecca C, Marjoram, Paul, Comai, Lucio, Reddy, Sita
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-07-2011; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Antibiotics, Antineoplastic - pharmacology; Cell Nucleus - metabolism; Cytoplasm; Cytoplasm - metabolism; Developmental biology; Dystrophy; EMBO24; Fatty Acids, Unsaturated - pharmacology; Gene expression; Gene Expression Regulation; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Inactivation; MINT; Molecular biology; Muscular dystrophy; Myoblasts - metabolism; myotonic dystrophy; Myotonic Dystrophy - genetics; Myotonic Dystrophy - physiopathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Transport - drug effects; Ribonucleic acid; RNA; RNA - metabolism; RNA Splicing - genetics; RNA-Binding Proteins - metabolism; Scientific Report; Scientific Reports; SHARP; Spen; transcription; Trinucleotide Repeat Expansion - genetics; myotonic dystrophy; Spen; SHARP; transcription; MINT
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2011.86

We describe a new mechanism by which CTG tract expansion affects myotonic dystrophy (DM1). Changes to the levels of a panel of RNAs involved in muscle development and function that are downregulated in DM1 are due to aberrant localization of the transcription factor SHARP (SMART/HDAC1‐associated repressor protein). Mislocalization of SHARP in DM1 is consistent with increased CRM1‐mediated export of SHARP to the cytoplasm. A direct link between CTG repeat expression and SHARP mislocalization is demonstrated as expression of expanded CTG repeats in normal cells recapitulates cytoplasmic SHARP localization. These results demonstrate a role for the inactivation of SHARP transcription in DM1 biology.
This study shows that in myotonic dystrophy (DM1) muscle the transcription factor SHARP is aberrantly localized to the cytoplasm, which results in the downregulation of several mRNAs involved in muscle development and function.