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<p>Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, among which non-syndromic TOF (nsTOF) represents the most common subtype; however, the molecular mechanisms underlying right ventricular outflow tract (RVOT) remodeling in nsTOF remain incompletely understood. Bulk transcriptomic and single-nucleus RNA sequencing (snRNA-seq) datasets derived from fetal and infant RVOT tissues were integrated for analysis. Differential expression, miRNA-mRNA regulatory network construction, protein–protein interaction analysis, functional enrichment, and pseudotime trajectory analyses were performed to identify candidate hub genes and dynamic transcriptional alterations associated with nsTOF. A total of 842 differentially expressed mRNAs and 66 differentially expressed miRNAs were identified. Integration analyses yielded a regulatory network containing 54 DE-miRNAs and 538 DE-mRNAs. Fourteen hub genes, including <i>PSMD14</i>, <i>NDUFA5</i>, <i>RPS27L</i>, <i>MRPS16</i>, <i>FOS</i>, and <i>SNRNP70</i>, were identified through consensus topological filtering. Functional analyses suggested potential involvement of pathways related to protein homeostasis, ribosome-associated quality control, RNA splicing, mitochondrial metabolism, and stress-response signaling. snRNA-seq analysis demonstrated cell type-specific expression patterns of hub genes. Pseudotime analysis further suggested stage-dependent transcriptional alterations during RVOT remodeling. Integrated multi-omics analysis identified 14 candidate hub genes potentially involved in RVOT remodeling in nsTOF. These findings suggest that dysregulation of protein homeostasis, RNA-processing pathways, and mitochondrial metabolic processes may contribute to nsTOF pathology. Further experimental validation is required to confirm these observations.</p>

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Integrative analysis of bulk and single-nucleus transcriptomes suggests proteostasis- and metabolism-related alterations in the right ventricular outflow tract of non-syndromic Tetralogy of Fallot

  • 期刊论文

  • 发表日期：

    2026年6月3日

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  • Hongpan Wang,
  • Xin Yong,
  • Yuyang Gao,
  • Wenyan Li,
  • Zhiyu Chen,
  • Zhen Liu,
  • Wenli Xu

摘要

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, among which non-syndromic TOF (nsTOF) represents the most common subtype; however, the molecular mechanisms underlying right ventricular outflow tract (RVOT) remodeling in nsTOF remain incompletely understood. Bulk transcriptomic and single-nucleus RNA sequencing (snRNA-seq) datasets derived from fetal and infant RVOT tissues were integrated for analysis. Differential expression, miRNA-mRNA regulatory network construction, protein–protein interaction analysis, functional enrichment, and pseudotime trajectory analyses were performed to identify candidate hub genes and dynamic transcriptional alterations associated with nsTOF. A total of 842 differentially expressed mRNAs and 66 differentially expressed miRNAs were identified. Integration analyses yielded a regulatory network containing 54 DE-miRNAs and 538 DE-mRNAs. Fourteen hub genes, including PSMD14, NDUFA5, RPS27L, MRPS16, FOS, and SNRNP70, were identified through consensus topological filtering. Functional analyses suggested potential involvement of pathways related to protein homeostasis, ribosome-associated quality control, RNA splicing, mitochondrial metabolism, and stress-response signaling. snRNA-seq analysis demonstrated cell type-specific expression patterns of hub genes. Pseudotime analysis further suggested stage-dependent transcriptional alterations during RVOT remodeling. Integrated multi-omics analysis identified 14 candidate hub genes potentially involved in RVOT remodeling in nsTOF. These findings suggest that dysregulation of protein homeostasis, RNA-processing pathways, and mitochondrial metabolic processes may contribute to nsTOF pathology. Further experimental validation is required to confirm these observations.