Long-read RNA sequencing reveals full-length HERV transcripts and novel ERVE-4 isoforms with potential immunotherapeutic relevance in clear cell renal cell carcinoma
Abstract
IntroductionHuman endogenous retroviruses (HERVs) are increasingly recognized as sources of tumor-associated antigens and potential targets for cellular immunotherapy. However, their repetitive sequences and noncanonical splicing patterns complicate accurate transcript annotation using common short-read RNA sequencing. This study aimed to improve HERV transcriptome annotation using long-read RNA sequencing.MethodsWe developed a bioinformatics workflow for comprehensive annotation of HERV expression using long-read RNA sequencing, with validation using short-read RNA sequencing. We applied this workflow to ERVE-4, a HERV element previously shown to be selectively expressed in clear cell renal cell carcinoma (ccRCC) and to encode immunogenic peptides currently under clinical investigation as targets for cellular immunotherapy.ResultsLong-read sequencing captured full-length HERV transcripts, improved mapping across repetitive regions, and enabled reconstruction of HERV isoforms. The workflow identified hundreds of HERV loci in long-read datasets absent from corresponding short-read annotations. Analysis of ERVE-4 revealed previously uncharacterized isoforms, whose expression was validated across multiple ccRCC tumors using RT-dPCR.DiscussionLong-read RNA sequencing improves the resolution and completeness of HERV transcriptome annotation. Novel ERVE-4 isoforms substantially expand the known antigenic coding potential of ERVE-4 possibly implying discovery of novel peptide targets for immunotherapy in ccRCC.
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BibTeX
@article{cherkasova2026longread,
title = {{Long-read RNA sequencing reveals full-length HERV transcripts and novel ERVE-4 isoforms with potential immunotherapeutic relevance in clear cell renal cell carcinoma}},
author = {Elena A. Cherkasova and Thomas Hill and Stefan Barisic and Long Chen and Jamie Diemer and Neelam Redekar and Richard W. Childs},
journal = {Frontiers in Molecular Biosciences},
year = {2026},
month = oct,
doi = {10.3389/fmolb.2026.1941192},
url = {https://www.frontiersin.org/articles/10.3389/fmolb.2026.1941192},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Long-read RNA sequencing reveals full-length HERV transcripts and novel ERVE-4 isoforms with potential immunotherapeutic relevance in clear cell renal cell carcinoma
AU - Elena A. Cherkasova
AU - Thomas Hill
AU - Stefan Barisic
AU - Long Chen
AU - Jamie Diemer
AU - Neelam Redekar
AU - Richard W. Childs
PY - 2026
DA - 2026/10/29
JO - Frontiers in Molecular Biosciences
DO - 10.3389/fmolb.2026.1941192
UR - https://www.frontiersin.org/articles/10.3389/fmolb.2026.1941192
AB - IntroductionHuman endogenous retroviruses (HERVs) are increasingly recognized as sources of tumor-associated antigens and potential targets for cellular immunotherapy. However, their repetitive sequences and noncanonical splicing patterns complicate accurate transcript annotation using common short-read RNA sequencing. This study aimed to improve HERV transcriptome annotation using long-read RNA sequencing.MethodsWe developed a bioinformatics workflow for comprehensive annotation of HERV expression using long-read RNA sequencing, with validation using short-read RNA sequencing. We applied this workflow to ERVE-4, a HERV element previously shown to be selectively expressed in clear cell renal cell carcinoma (ccRCC) and to encode immunogenic peptides currently under clinical investigation as targets for cellular immunotherapy.ResultsLong-read sequencing captured full-length HERV transcripts, improved mapping across repetitive regions, and enabled reconstruction of HERV isoforms. The workflow identified hundreds of HERV loci in long-read datasets absent from corresponding short-read annotations. Analysis of ERVE-4 revealed previously uncharacterized isoforms, whose expression was validated across multiple ccRCC tumors using RT-dPCR.DiscussionLong-read RNA sequencing improves the resolution and completeness of HERV transcriptome annotation. Novel ERVE-4 isoforms substantially expand the known antigenic coding potential of ERVE-4 possibly implying discovery of novel peptide targets for immunotherapy in ccRCC.
SN - 2296-889X
ER -