Document Type

Article

Publication Date

2-22-2025

Publication Title

Mob DNA

Keywords

JGM

JAX Source

Mob DNA. 2025;16(1):6.

Volume

16

Issue

1

First Page

6

Last Page

6

ISSN

1759-8753

PMID

39987084

DOI

https://doi.org/10.1186/s13100-025-00341-4

Grant

This work was supported by start-up funds from the Jackson Laboratory to C.R.B., J.B., and O.A. as well as start-up funds from the University of Connecticut Health Center to C.R.B. Support was also provided by National Institutes of Health grants R00GM120453 and R35GM133600 from the National Institute of General Medical Sciences to C.R.B.

Abstract

Transposable elements (TEs) drive genome evolution and can affect gene expression through diverse mechanisms. In breast cancer, disrupted regulation of TE sequences may facilitate tumor-specific transcriptomic alterations. We examine 142,514 full-length isoforms derived from long-read RNA sequencing (LR-seq) of 30 breast samples to investigate the effects of TEs on the breast cancer transcriptome. Approximately half of these isoforms contain TE sequences, and these contribute to half of the novel annotated splice junctions. We quantify splicing of these LR-seq derived isoforms in 1,135 breast tumors from The Cancer Genome Atlas (TCGA) and 1,329 healthy tissue samples from the Genotype-Tissue Expression (GTEx), and find 300 TE-overlapping tumor-specific splicing events. Some splicing events are enriched in specific breast cancer subtypes - for example, a TE-driven transcription start site upstream of ERBB2 in HER2 + tumors, and several TE-mediated splicing events are associated with patient survival and poor prognosis. The full-length sequences we capture with LR-seq reveal thousands of isoforms with signatures of RNA editing, including a novel isoform belonging to RHOA; a gene previously implicated in tumor progression. We utilize our full-length isoforms to discover polymorphic TE insertions that alter splicing and validate one of these events in breast cancer cell lines. Together, our results demonstrate the widespread effects of dysregulated TEs on breast cancer transcriptomes and highlight the advantages of long-read isoform sequencing for understanding TE biology. TE-derived isoforms may alter the expression of genes important in cancer and can potentially be used as novel, disease-specific therapeutic targets or biomarkers.One sentence summary: Transposable elements generate alternative isoforms and alter post-transcriptional regulation in human breast cancer.

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