HnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

Junqiang Ye, Nadine Beetz, Sean O'Keeffe, Juan Carlos Tapia, Lindsey Macpherson, Weisheng V. Chen, Rhonda Bassel-Duby, Eric N. Olson, Tom Maniatis

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.

Original languageEnglish (US)
Pages (from-to)E3020-E3029
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number23
DOIs
StatePublished - Jun 9 2015

Fingerprint

RNA Precursors
Heterogeneous-Nuclear Ribonucleoprotein U
Excitation Contraction Coupling
Alternative Splicing
Proteins
Cardiac Myocytes
Connectin
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Asparagine
Dilated Cardiomyopathy
Protein Isoforms
RNA

Keywords

  • Alternative splicing
  • Dilated cardiomyopathy
  • Heart development
  • N-glycosylation
  • RNA-seq

ASJC Scopus subject areas

  • General

Cite this

HnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function. / Ye, Junqiang; Beetz, Nadine; O'Keeffe, Sean; Tapia, Juan Carlos; Macpherson, Lindsey; Chen, Weisheng V.; Bassel-Duby, Rhonda; Olson, Eric N.; Maniatis, Tom.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 23, 09.06.2015, p. E3020-E3029.

Research output: Contribution to journalArticle

Ye, Junqiang ; Beetz, Nadine ; O'Keeffe, Sean ; Tapia, Juan Carlos ; Macpherson, Lindsey ; Chen, Weisheng V. ; Bassel-Duby, Rhonda ; Olson, Eric N. ; Maniatis, Tom. / HnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 23. pp. E3020-E3029.
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