Zheng et al. 2023 (PRJNA807729)

General Details

Title CRISPR/Cas9-mediated gene knockout screen uncovers novel open reading frames encoded in lncRNA regulating ER+ breast cancer progression
Organism
Number of Samples 3
Release Date 2022/02/16 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP360229
ENA SRP360229
GEO GSE196927
BioProject PRJNA807729

Publication

Title
Authors Zheng C, Wei Y, Zhang P, Xu L, Zhang Z, Lin K, Hou J, Lv X, Ding Y, Chiu Y, Jain A, Islam N, Malovannaya A, Wu Y, Ding F, Xu H, Sun M, Chen X, Chen Y
Journal The Journal of clinical investigation
Publication Date 2023 Mar 1
Abstract Emerging evidence suggests that cryptic translation within long noncoding RNAs (lncRNAs) may produce novel proteins with important developmental/physiological functions. However, the role of this cryptic translation in complex diseases (e.g., cancer) remains elusive. Here, we applied an integrative strategy combining ribosome profiling and CRISPR/Cas9 screening with large-scale analysis of molecular/clinical data for breast cancer (BC) and identified estrogen receptor α-positive (ER+) BC dependency on the cryptic ORFs encoded by lncRNA genes that were upregulated in luminal tumors. We confirmed the in vivo tumor-promoting function of an unannotated protein, GATA3-interacting cryptic protein (GT3-INCP) encoded by LINC00992, the expression of which was associated with poor prognosis in luminal tumors. GTE-INCP was upregulated by estrogen/ER and regulated estrogen-dependent cell growth. Mechanistically, GT3-INCP interacted with GATA3, a master transcription factor key to mammary gland development/BC cell proliferation, and coregulated a gene expression program that involved many BC susceptibility/risk genes and impacted estrogen response/cell proliferation. GT3-INCP/GATA3 bound to common cis regulatory elements and upregulated the expression of the tumor-promoting and estrogen-regulated BC susceptibility/risk genes MYB and PDZK1. Our study indicates that cryptic lncRNA-encoded proteins can be an important integrated component of the master transcriptional regulatory network driving aberrant transcription in cancer, and suggests that the 'hidden' lncRNA-encoded proteome might be a new space for therapeutic target discovery.
PMC PMC9974104
PMID 36856111
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR18054549 PRJNA807729 Homo sapiens MCF7 Ribo-Seq 0.0
SRR18054548 PRJNA807729 Homo sapiens MCF7 Ribo-Seq 0.0
SRR18054547 PRJNA807729 Homo sapiens MCF7 Ribo-Seq 0.0
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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