Faculty, Staff and Student Publications
Publication Date
2-21-2025
Journal
Science Advances
Abstract
The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.
Keywords
Humans, Mutation, Neoplasms, Conserved Sequence, MicroRNAs, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, RNA, Untranslated, Cell Proliferation, Animals, Mice
DOI
10.1126/sciadv.ado2830
PMID
39970212
PMCID
PMC11837999
PubMedCentral® Posted Date
2-19-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
