Omics · study · 2026
Fitness landscape of the MYC locus and a druggable ultraconserved RNA element revealed by CRISPR saturation mutagenesis (RNA-seq, ChIP-seq)
Listed in NCBI GEO
The genome is composed of relatively rare, typically conserved coding sequences and abundant, often less conserved noncoding sequences.
Description
The relative contributions of coding and noncoding regions to genetic information remain poorly understood. Here, we present a base-pair–resolution fitness landscape of the 10-kb MYC locus generated by CRISPR saturation mutagenesis using a near-PAMless, high-fidelity SpRY-Cas9.
This unbiased analysis revealed that most (67%) functionally critical sequences are noncoding. Paradoxically, the phenotypic impact of noncoding sequences correlates inversely with evolutionary conservation, in part driven by rapidly evolving cis-regulatory DNA elements. We identified an ultraconserved 3’ UTR element required for cell growth in MYC-dependent cancer cells.
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Strikingly, targeting this RNA element with steric-blocking antisense oligonucleotides (ASOs) selectively eliminates MYC-dependent cancer cells by suppressing MYC function without reducing MYC protein abundance. Mechanistically, this 3′ UTR element promotes perinuclear localization of MYC mRNA, facilitating perinuclear translation and nuclear import of the short-lived MYC protein, enabling its function as a nuclear transcription factor.
Together, these findings highlight noncoding sequences as key carriers of genetic information, define the functional architecture of the MYC locus, and uncover cancer-inhibitory ASOs targeting an RNA element
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE317nnn/GSE317096 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE317096 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1405774 ncbi.nlm.nih.gov/bioproject/PRJNA1405774 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Genome binding/occupancy profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · RNA sequencing 65%
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE317096 | 14 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[method].geo_series_type:genome-binding-occupancy-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |