HnRNP M facilitates exon 7 inclusion of SMN2 pre-mRNA in spinal muscular atrophy by targeting an enhancer on exon 7

Sunghee Cho, Heegyum Moon, Tiing Jen Loh, Huyn Kyung Oh, Sungchan Cho, Hyon E. Choy, Woo Keun Song, Jang Soo Chun, Xuexiu Zheng, Haihong Shen

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30 Citations (Scopus)

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease, which causes death of motor neurons in the anterior horn of the spinal cord. Genetic cause of SMA is the deletion or mutation of SMN1 gene, which encodes the SMN protein. Although SMA patients include SMN2 gene, a duplicate of SMN1 gene, predominant production of exon 7 skipped isoform from SMN2 pre-mRNA, fails to rescue SMA patients. Here we show that hnRNP M, a member of hnRNP protein family, when knocked down, promotes exon 7 skipping of both SMN2 and SMN1 pre-mRNA. By contrast, overexpression of hnRNP M promotes exon 7 inclusion of both SMN2 and SMN1 pre-mRNA. Significantly, hnRNP M promotes exon 7 inclusion in SMA patient cells. Thus, we conclude that hnRNP M promotes exon 7 inclusion of both SMN1 and SMN2 pre-mRNA. We also demonstrate that hnRNP M contacts an enhancer on exon 7, which was previously shown to provide binding site for tra2β. We present evidence that hnRNP M and tra2β contact overlapped sequence on exon 7 but with slightly different RNA sequence requirements. In addition, hnRNP M promotes U2AF65 recruitment on the flanking intron of exon 7. We conclude that hnRNP M promotes exon 7 inclusion of SMN1 and SMN2 pre-mRNA through targeting an enhancer on exon 7 through recruiting U2AF65. Our results provide a clue that hnRNP M is a potential therapeutic target for SMA.

Original languageEnglish
Pages (from-to)306-315
Number of pages10
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1839
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

Keywords

  • Exon 7
  • HnRNP M
  • Pre-mRNA splicing
  • SMN2
  • Spinal muscular atrophy

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