title: Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development.
abstract: During postnatal development the heart undergoes a rapid and dramatic transition to adult function through transcriptional and post-transcriptional mechanisms, including alternative splicing (AS). Here we perform deep RNA-sequencing on RNA from cardiomyocytes and cardiac fibroblasts to conduct a high-resolution analysis of transcriptome changes during postnatal mouse heart development. We reveal extensive changes in gene expression and AS that occur primarily between postnatal days 1 and 28. Cardiomyocytes and cardiac fibroblasts show reciprocal regulation of gene expression reflecting differences in proliferative capacity, cell adhesion functions and mitochondrial metabolism. We further demonstrate that AS plays a role in vesicular trafficking and membrane organization. These AS transitions are enriched among targets of two RNA-binding proteins, Celf1 and Mbnl1, which undergo developmentally regulated changes in expression. Vesicular trafficking genes affected by AS during normal development (when Celf1 is downregulated) show a reversion to neonatal splicing patterns after Celf1 re-expression in adults. Short-term Celf1 induction in adult animals results in disrupted transverse tubule organization and calcium handling. These results identify potential roles for AS in multiple aspects of postnatal heart maturation, including vesicular trafficking and intracellular membrane dynamics.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jimena
authors.initials: J
authors.lastname: Giudice
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: 1] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wang
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Scavuzzo
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [3].
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Ward
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [2].
authors.forename: Auinash
authors.initials: A
authors.lastname: Kalsotra
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 1] Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas 77030, USA [2] Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Division of Biostatistics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: 1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [3] Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Texas 77030, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D000067879:CELF1 Protein; D004268:DNA-Binding Proteins / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics; D017423:Sequence Analysis, RNA; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D033921:Vesicular Transport Proteins
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