Decoding proteomic complexity of transcript variants and homologous isoforms for precision therapeutics
5 affiliations
- 1Department of Pharmacology, Pusan National University School of Medicine Yangsan 50612 Korea
- 2Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine Busan 49241 Korea
- 3Biomedical Research Institute, Pusan National University Hospital Busan 49241 Korea
- 4Medical Research Institute, Pusan National University Yangsan 50612 Korea
- 5Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital Yangsan 50612 Korea
Abstract
The traditional "one gene, one protein" paradigm is insufficient to capture the vast phenotypic and physiological complexity of eukaryotes. This review aims to comprehensively elucidate the molecular mechanisms of transcriptomic diversification, namely, alternative splicing, alternative usage of promoter, and alternative polyadenylation, and their profound impacts on cellular homeostasis and human disease. By synthesizing recent breakthroughs in targeted long-read RNA sequencing, single-cell isoform-specific multiomics, and AI-driven 3D structural modeling, we systematically examine how transcript variants are generated and functionally annotated. Our analysis highlights that multiple transcript variants originating from a single genetic locus are not merely redundant copies; rather, subtle sequence alterations dynamically rewire protein-protein interaction networks and dictate precise subcellular localization. The exquisite spatiotemporal regulation of these variants controls critical cell fate decisions and organ development. Consequently, the pathological dysregulation of these processes, frequently termed spliceopathies, acts as a primary driver in severe pathologies, including cancer multidrug resistance, metabolic reprogramming, and neurodegenerative disorders. In conclusion, understanding the eukaryotic proteome requires a fundamental shift from conventional gene-level to isoform-level perspectives. Decoding the complex regulatory syntax of transcript variants paves the way for next-generation precision medicine, highlighting the therapeutic potential of RNA-targeted interventions, such as antisense oligonucleotides and CRISPR-based RNA editing, to correct pathogenic isoforms.
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BibTeX
@article{kum2026decoding,
title = {{Decoding proteomic complexity of transcript variants and homologous isoforms for precision therapeutics}},
author = {Seo A Kum and Hong Koo Ha and Sun Sik Bae},
journal = {The Korean Journal of Physiology \& Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology},
year = {2026},
month = nov,
doi = {10.4196/kjpp.26.299},
url = {https://doi.org/10.4196/kjpp.26.299},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Decoding proteomic complexity of transcript variants and homologous isoforms for precision therapeutics
AU - Seo A Kum
AU - Hong Koo Ha
AU - Sun Sik Bae
PY - 2026
DA - 2026/11/01
JO - The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology
DO - 10.4196/kjpp.26.299
UR - https://doi.org/10.4196/kjpp.26.299
AB - The traditional "one gene, one protein" paradigm is insufficient to capture the vast phenotypic and physiological complexity of eukaryotes. This review aims to comprehensively elucidate the molecular mechanisms of transcriptomic diversification, namely, alternative splicing, alternative usage of promoter, and alternative polyadenylation, and their profound impacts on cellular homeostasis and human disease. By synthesizing recent breakthroughs in targeted long-read RNA sequencing, single-cell isoform-specific multiomics, and AI-driven 3D structural modeling, we systematically examine how transcript variants are generated and functionally annotated. Our analysis highlights that multiple transcript variants originating from a single genetic locus are not merely redundant copies; rather, subtle sequence alterations dynamically rewire protein-protein interaction networks and dictate precise subcellular localization. The exquisite spatiotemporal regulation of these variants controls critical cell fate decisions and organ development. Consequently, the pathological dysregulation of these processes, frequently termed spliceopathies, acts as a primary driver in severe pathologies, including cancer multidrug resistance, metabolic reprogramming, and neurodegenerative disorders. In conclusion, understanding the eukaryotic proteome requires a fundamental shift from conventional gene-level to isoform-level perspectives. Decoding the complex regulatory syntax of transcript variants paves the way for next-generation precision medicine, highlighting the therapeutic potential of RNA-targeted interventions, such as antisense oligonucleotides and CRISPR-based RNA editing, to correct pathogenic isoforms.
SN - 1226-4512
SN - 2093-3827
ER -