Abstract
The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly up-regulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is mis-regulated.
Highlights
Celf[1] protein expression patterns during development are conserved in the chicken and mouse[14]
Celf[1] mRNA levels at postnatal day 3 (PN3) were decreased 20-fold in Celf1 −/−hearts based on RNA-seq data
The analysis revealed that Celf1-CLIP tags are significantly more prevalent in 3′UTRs of the regulated cell cycle genes compared to the set of control genes that are not affected by Celf[1] loss of function (Fig. 6b)
Summary
Celf[1] protein expression patterns during development are conserved in the chicken and mouse[14]. In heart Celf[1] protein expression levels are high during embryogenesis and the perinatal period, start to decrease at postnatal (PN) day 6–7, and at adult stages are dramatically reduced[14,15]. This developmental down-regulation of Celf[1] protein correlates with coordinated alternative splicing transitions that occur between birth and adulthood[15]. We previously demonstrated that transgenic over-expression of human CELF1 in cardiomyoctes in adult mice leads to severe cardiac failure These animals exhibit extensive mis-regulation of alternative splicing and gene expression developmental networks[15,16,17,18]. These genes are enriched for Celf[1] binding sites based on CLIP-seq data supporting a regulatory role for Celf[1] at neonatal stages in regulating the stability of mRNAs from cell cycle genes
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