Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Developmental Biology

Background:

• The RNA binding protein Celf1 (CELF-1) is crucial for regulating RNA processing, including alternative splicing, mRNA stability, and translation.
• Celf1 expression is significantly reduced during mouse heart development, and its re-expression in adults leads to heart failure and a reversion to fetal gene expression patterns.
• The specific effects of Celf1 depletion on neonatal cardiac transcriptional and posttranscriptional regulation remain largely uncharacterized.

Purpose of the Study:

• To investigate the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonatal mice.
• To identify the network of genes regulated by Celf1 in the neonatal heart.
• To elucidate the mechanisms by which Celf1 controls gene expression during early cardiac development.

Main Methods:

• Utilized RNA-sequencing (RNA-seq) to analyze mRNA expression profiles in homozygous Celf1 knock-out neonatal mouse hearts.
• Bioinformatic analysis to identify significantly up-regulated and down-regulated gene networks.
• Investigated Celf1 binding sites on target transcripts to confirm regulatory roles.

Main Results:

• Homozygous Celf1 knock-out neonates displayed cardiac dysfunction, despite being smaller than wild-type littermates.
• RNA-seq revealed significant up-regulation of cell cycle genes and down-regulation of ion transport and circadian genes in neonatal Celf1-deficient hearts.
• Cell cycle gene networks showed enrichment for Celf1 binding sites, suggesting Celf1 regulates their mRNA stability.
• A cardiac splicing network was identified, with target splicing events containing multiple Celf1 binding sites and GU-rich motifs.

Conclusions:

• Celf1 plays a critical role in maintaining neonatal cardiac function and regulating gene expression networks.
• Celf1 depletion in neonates leads to distinct transcriptional and posttranscriptional changes, including altered cell cycle control and ion transport.
• Understanding Celf1's direct targets is essential for deciphering developmental gene regulation and the pathophysiology of Celf1-associated diseases.