Omics · study · 2026
Targeted Transcriptional Repression by Induced Proximity
Listed in NCBI GEO
Most cancer-driving proteins remain “undruggable” due to the absence of ligandable pockets and their reliance on intrinsically disordered or protein–DNA/protein–protein interactions.
Description
Transcription factors, which orchestrate oncogenic gene expression programs, are particularly challenging: they turnover rapidly, evade durable pharmacological inhibition, and resist even emerging targeted protein-degradation strategies. Here, we describe a new induced-proximity therapeutic modality, Transcriptional Repression via Active Chemical Epigenetic Reprogramming (TRACER), that enforces locus-specific transcriptional silencing by recruiting endogenous corepressor complexes to transcription factor binding sites.
We developed small-molecule TRACERs that tether methyl-CpG binding domain protein 2 (MBD2) and the Nucleosome Remodelling and Deacetylase (NuRD) complex to transcription factor–directed ligands. An estrogen receptor (ER) TRACER potently suppressed ER transcriptional activity in breast cancer cells, downregulated canonical ER target genes, and required MBD2 and histone deacetylase (HDAC1/2) for activity, confirming on-target epigenetic repression.
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Extending this approach to prostate cancer, an androgen receptor (AR) TRACER transcriptionally repressed both full-length AR and the drug-resistant truncation variant AR-V7, achieving >90% inhibition of AR transcriptional activity in androgen-independent prostate cancer cells with locus-specific gene repression. We further show that TRACERs can be modularly reprogrammed to recruit alternative repressors, including PRC2.
Collectively, these findings establish TRACERs as a generalizable modality to pharmacologically silence undruggable transcription factors through targeted epigenetic reprogramming, offering a powerful new strategy for treating cancers refractory to existing therapies.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE332nnn/GSE332560 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332560 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1468603 ncbi.nlm.nih.gov/bioproject/PRJNA1468603 ↗
project · from NCBI GEO
- PubMed 42500035 pubmed.ncbi.nlm.nih.gov/42500035 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Genome binding/occupancy profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE332560 | 13 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:genome-binding-occupancy-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| 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 |