Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2

Ioannis Grammatikakis, Peisu Zhang, Amaresh C. Panda, Jiyoung Kim, Stuart Maudsley, Kotb Abdelmohsen, Xiaoling Yang, Jennifer L. Martindale, Omar Motiño, Emmette R. Hutchison, Mark P. Mattson, Myriam Gorospe

Research output: Contribution to journalArticle

Abstract

During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. Accordingly, HNRNPH levels decline while TRF2-S levels increase during neuronal differentiation. In addition, CRISPR/Cas9-mediated deletion of hnRNPH2 selectively accelerates the NGF-triggered differentiation of rat pheochromocytoma cells into neurons. In sum, HNRNPH is a splicing regulator of Trf2 pre-mRNA that prevents the expression of TRF2-S, a factor implicated in neuronal differentiation. Neuronal differentiation is triggered by a change in TRF2 splice forms from full-length (FL) to short (S). Grammatikakis et al. find that the RNA-binding protein and splicing regulator HNRNPH prevents this switch, elevating TRF2-FL and inhibiting neurogenesis in rat. Accordingly, HNRNPH silencing leads to accumulation of TRF2-S and enhances neuronal differentiation.

Original languageEnglish (US)
Pages (from-to)926-934
Number of pages9
JournalCell Reports
Volume15
Issue number5
DOIs
StatePublished - May 3 2016
Externally publishedYes

Keywords

  • Alternative splicing
  • HNRNPH
  • MRNA
  • Ribonucleoprotein complex
  • TRF2
  • TRF2-S

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Grammatikakis, I., Zhang, P., Panda, A. C., Kim, J., Maudsley, S., Abdelmohsen, K., Yang, X., Martindale, J. L., Motiño, O., Hutchison, E. R., Mattson, M. P., & Gorospe, M. (2016). Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2. Cell Reports, 15(5), 926-934. https://doi.org/10.1016/j.celrep.2016.03.080