MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1

Kino, Yoshihiro; Washizu, Chika; Oma, Yoko; Onishi, Hiroaki; Nezu, Yuriko; Sasagawa, Noboru; Nukina, Nobuyuki; Ishiura, Shoichi

doi:10.1093/nar/gkp681

Cited by 84 publications

(86 citation statements)

References 56 publications

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“…S5C). Muscleblind-like protein 1 (MBNL1) is highly expressed in cardiac and skeletal muscles (52) and is a known regulator of mRNA splicing in these tissues (53,54). Intron retention has emerged as a widespread mechanism to regulate gene expression in different cell and tissue types as well as during stem cell differentiation (42,55,56).…”

Section: Discussionmentioning

confidence: 99%

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Tahmasebi

Jafarnejad

Tam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tractbinding protein 1 (PTBP1) promotes the retention of an intron in the 5′-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.mRNA translation | 4E-BPs | PTBP | embryonic stem cell | YY2

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Section: Discussionmentioning

confidence: 99%

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Tahmasebi

Jafarnejad

Tam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In intron 4 of the MBNL1 pre-mRNA, we observed that MBNL1 regulates exon 5 exclusion by binding a response element located within an AGEZ just downstream of a distant branch point and PY tract. In the CLCN1 pre-mRNA, MBNL1 represses exon 7A inclusion by binding the 5Ј-end of exon 7A (which contains an exonic splicing enhancer) and flanking intronic regions (42). Previously, we showed that MBNL1 and U2AF65 compete for binding at the 3Ј-end of intron 4 of the TNNT2 pre-mRNA to regulate exon 5.…”

Section: Polypyrimidine Tract-binding Protein 1 (Ptb1) and Mbnl1 Negamentioning

confidence: 99%

Autoregulated Splicing of muscleblind-like 1 (MBNL1) Pre-mRNA

Gates

Coonrod

Berglund

2011

Journal of Biological Chemistry

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Muscleblind-like 1 (MBNL1) is a splicing factor whose improper cellular localization is a central component of myotonic dystrophy. In myotonic dystrophy, the lack of properly localized MBNL1 leads to missplicing of many pre-mRNAs. One of these events is the aberrant inclusion of exon 5 within the MBNL1 pre-mRNA. The region of the MBNL1 gene that includes exon 5 and flanking intronic sequence is highly conserved in vertebrate genomes. The 3 -end of intron 4 is noncanonical in that it contains a predicted branch point that is 141 nucleotides from the 3 -splice site and an AAG 3 -splice site. Using a minigene that includes exon 4, intron 4, exon 5, intron 5, and exon 6 of MBNL1, we showed that MBNL1 regulates inclusion of exon 5. Mapping of the intron 4 branch point confirmed that branching occurs primarily at the predicted distant branch point. Structure probing and footprinting revealed that the highly conserved region between the branch point and 3 -splice site is primarily unstructured and that MBNL1 binds within this region of the pre-mRNA. Deletion of the MBNL1 response element eliminated MBNL1 splicing regulation and led to complete inclusion of exon 5, which is consistent with the suppressive effect of MBNL1 on splicing.Splicing of pre-mRNAs is an important event that contributes to a diverse proteome as well as the regulation of gene expression. It is estimated that more than 90% of human genes undergo alternative splicing (1, 2). To produce a functional mRNA, non-coding regions must be accurately removed, and the coding regions must be ligated together. Splicing occurs via two transesterification reactions that result in removal of the intron and ligation of the exons. This splicing mechanism relies on pre-mRNA sequences, proteins, and small nuclear RNAs (snRNAs) that are necessary for intron and exon definition and the two transesterification reactions. Cis-sequences that are important for splicing include the 5Ј-splice site (ss), 2 the branch point sequence, the polypyrimidine (PY) tract, and the 3Ј-ss. These canonical intronic motifs, plus additional regulatory splicing motifs found in exons and introns, are recognized by splicing factors and small nuclear ribonucleoproteins (U1, U2, U4, U5, and U6) to form the spliceosome, which catalyzes intron removal (for a review, see Ref.3).There are many splicing factors that are only involved in a subset of splicing decisions. These include the human muscleblind-like family of RNA-binding proteins: MBNL1/2/3 also known as MBNL/EXP, MBLL/MPL1, and MBXL/CHCR, respectively. The founding member of this family, muscleblind (Mbl), was discovered in Drosophila and was shown to be important for photoreceptor differentiation and terminal differentiation of muscles (4, 5). Subsequently, MBNL proteins were found to associate with expanded CUG repeats (located in the 3Ј-untranslated region of the DMPK gene) that have been shown to act as a toxic RNA and are at least partially responsible for causing myotonic dystrophy (DM) type 1 (for reviews, see Refs. 6 -8). The expanded...

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“…The muscleblind splicing regulatory factor Mbnl1 has been directly implicated in the causation of DM1 because it binds CUG repeats, colocalizes with CUG-repeat RNA foci and regulates the alternative splicing of genes mis-spliced in DM1 patients (Fardaei et al, 2002;Ho et al, 2004;Kino et al, 2009;Mankodi et al, 2001;Osborne et al, 2009). Altered mRNA splicing has been reported in more than 20 genes in DM1 patients (Kalsotra et al, 2008;Lin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats

Querido

Gallardo

Beaudoin

et al. 2011

Journal of Cell Science

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SummaryTranscripts containing expanded CNG repeats, which are found in several neuromuscular diseases, are not exported from the nucleus and aggregate as ribonuclear inclusions by an unknown mechanism. Using the MS2-GFP system, which tethers fluorescent proteins to a specific mRNA, we followed the dynamics of single CUG-repeat transcripts and RNA aggregation in living cells. Single transcripts with 145 CUG repeats from the dystrophia myotonica-protein kinase (DMPK) gene had reduced diffusion kinetics compared with transcripts containing only five CUG repeats. Fluorescence recovery after photobleaching (FRAP) experiments showed that CUGrepeat RNAs display a stochastic aggregation behaviour, because individual RNA foci formed at different rates and displayed different recoveries. Spontaneous clustering of CUG-repeat RNAs was also observed, confirming the stochastic aggregation revealed by FRAP. The splicing factor Mbnl1 colocalized with individual CUG-repeat transcripts and its aggregation with RNA foci displayed the same stochastic behaviour as CUG-repeat mRNAs. Moreover, depletion of Mbnl1 by RNAi resulted in decreased aggregation of CUG-repeat transcripts after FRAP, supporting a direct role for Mbnl1 in CUG-rich RNA foci formation. Our data reveal that nuclear CUG-repeat RNA aggregates are labile, constantly forming and disaggregating structures, and that the Mbnl1 splicing factor is directly involved in the aggregation process.

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MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1

Cited by 84 publications

References 56 publications

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

Autoregulated Splicing of muscleblind-like 1 (MBNL1) Pre-mRNA

Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats

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