Post-Transcriptional Modification by Alternative Splicing and Pathogenic Splicing Variants in Cardiovascular Development and Congenital Heart Defects

Abstract

Advancements in genomics, bioinformatics, and genome editing have uncovered new dimensions in gene regulation. Post-transcriptional modifications by the alternative splicing of mRNA transcripts are critical regulatory mechanisms of mammalian gene expression. In the heart, there is an expanding interest in elucidating the role of alternative splicing in transcriptome regulation. Substantial efforts were directed toward investigating this process in heart development and failure. However, few studies shed light on alternative splicing products and their dysregulation in congenital heart defects (CHDs). While elegant reports showed the crucial roles of RNA binding proteins (RBPs) in orchestrating splicing transitions during heart development and failure, the impact of RBPs dysregulation or genetic variation on CHDs has not been fully addressed. Herein, we review the current understanding of alternative splicing and RBPs’ roles in heart development and CHDs. Wediscuss the impact of perinatal splicing transition and its dysregulation in CHDs. We further summarize the discoveries made of causal splicing variants in key transcription factors that are implicated in CHDs. An improved understanding of the roles of alternative splicing in heart development and CHDs may potentially inform novel preventive and therapeutic advancements for newborn infants with CHDs.

Development and disease-specific regulation of RNA splicing in cardiovascular system

“…These two families typically play opposing regulatory roles in splicing. In addition to SR and hnRNP proteins, RBPs containing RNA recognition motifs (RRM), K homology structural domains (KH), and zinc finger structural domains also play a significant role in alternative splicing regulation ( Mehta and Touma, 2023 ).…”

“…During cardiac development, RNA-binding proteins (RBPs) orchestrate the alternative splicing of sarcomere genes, so as to determine the structure and mechanical properties of cardiac muscle. Notably, Titin (TTN), the largest molecular spring in the heart encoded by 364 exons, is subjected to various alternative splicing events, thereby modulating the Titin-based passive tension, a determinant of diastolic function ( Mehta and Touma, 2023 ). Splicing dysfunction has been suggested to be implicated in multiple diseases ( Bonnal et al, 2020 ; Rogalska et al, 2023 ).…”