Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer

Authors

Giacomo Grillo
Tina Keshavarzian
Simon Linder
Christopher Arlidge
Lisanne Mout
Ankita Nand
Mona Teng
Aditi Qamra
Stanley Zhou
Ken J Kron
Alex Murison
James R Hawley
Michael Fraser
Theodorus H van der Kwast
Ganesh V Raj
Housheng Hansen He
Wilbert Zwart
Mathieu Lupien

Language

English

Publication Date

11-1-2023

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-23-0331

PMID

37694973

PMCID

PMC10618745

PubMedCentral® Posted Date

9-11-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Transposable elements hold regulatory functions that impact cell fate determination by controlling gene expression. However, little is known about the transcriptional machinery engaged at transposable elements in pluripotent and mature versus oncogenic cell states. Through positional analysis over repetitive DNA sequences of H3K27ac chromatin immunoprecipitation sequencing data from 32 normal cell states, we report pluripotent/stem and mature cell state–specific “regulatory transposable elements.” Pluripotent/stem elements are binding sites for pluripotency factors (e.g., NANOG, SOX2, OCT4). Mature cell elements are docking sites for lineage-specific transcription factors, including AR and FOXA1 in prostate epithelium. Expanding the analysis to prostate tumors, we identify a subset of regulatory transposable elements shared with pluripotent/stem cells, including Tigger3a. Using chromatin editing technology, we show how such elements promote prostate cancer growth by regulating AR transcriptional activity. Collectively, our results suggest that oncogenesis arises from lineage-specific transcription factors hijacking pluripotent/stem cell regulatory transposable elements.

Significance:

We show that oncogenesis relies on co-opting transposable elements from pluripotent stem cells as regulatory elements altering the recruitment of lineage-specific transcription factors. We further discover how co-option is dependent on active chromatin states with important implications for developing treatment options against drivers of oncogenesis across the repetitive DNA.

Keywords

Male, Humans, Transcription Factors, DNA Transposable Elements, Cell Differentiation, Chromatin, Prostatic Neoplasms, Carcinogenesis

Published Open-Access

yes

Recommended Citation

Grillo, Giacomo; Keshavarzian, Tina; Linder, Simon; et al., "Transposable Elements Are Co-opted as Oncogenic Regulatory Elements by Lineage-Specific Transcription Factors in Prostate Cancer" (2023). Faculty, Staff and Student Publications. 1193.
https://digitalcommons.library.tmc.edu/uthsph_docs/1193