Substantial unannotated noncoding transcripts in tumors may transcriptionally regulate cancer-related genes

Area of Science:

• Genomics
• Transcriptomics
• Cancer Biology

Background:

• Unannotated transcripts, including unannotated noncoding transcripts (UNTs), are abundant but poorly characterized.
• Functional roles of UNTs, particularly in disease, remain largely unknown.
• Previous studies hinted at functional UNTs in tumors, but lacked systematic investigation.

Purpose of the Study:

• To identify and characterize unannotated genes and transcripts in cancer.
• To investigate the regulatory mechanisms and functional roles of UNTs in cancer.
• To determine if UNTs can transcriptionally regulate gene expression.

Main Methods:

• Pan-cancer analysis of cell lines and tissues to identify unannotated transcripts.
• Prediction of DNA-binding domains (DBDs) in UNTs and DNA-binding sites (DBSs) in target gene promoters.
• CRISPR/Cas9 deletion of UNT DBDs in cancer cell lines, followed by RNA sequencing and phenotypic analysis.

Main Results:

• Identified numerous differentially expressed unannotated genes and transcripts.
• Demonstrated that UNT DBD deletion leads to significant differential gene expression and altered cell phenotypes.
• Revealed that UNTs can transcriptionally regulate target genes.

Conclusions:

• UNTs represent a significant class of transcriptional regulators in cancer.
• UNT-mediated transcriptional regulation is specific to cancer type and species.
• The specificity of UNTs offers potential for developing disease-specific therapeutic targets.