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Updated: Aug 5, 2026
10:44
In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing
Published on: May 5, 2023
Targeted Transcriptional Repression by Induced Proximity
Christian E Stieger1,2,3,4, Xinru Chen1,2,3, Christina C Kuismi1,2,3
1Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, United States.
ACS Central Science
|July 25, 2026
Summary
A new therapeutic approach called Transcriptional Repression via Active Chemical Epigenetic Reprogramming (TRACER) silences difficult transcription factors. TRACERs leverage epigenetic reprogramming to target cancer-driving proteins, offering new treatment options.
Area of Science:
- Epigenetics
- Molecular Biology
- Drug Discovery
Background:
- Transcription factors are challenging drug targets due to their structure and rapid turnover.
- Existing therapies are often ineffective against cancers driven by these 'undruggable' targets.
Purpose of the Study:
- To introduce a novel therapeutic modality, TRACER, for targeted transcriptional silencing.
- To demonstrate the efficacy of TRACERs in repressing key cancer-related transcription factors.
Main Methods:
- Developed small-molecule TRACERs to recruit the MBD2/NuRD complex to transcription factor binding sites.
- Utilized TRACERs targeting estrogen receptor (ER) in breast cancer cells.
- Applied TRACERs to androgen receptor (AR) and its variants (AR-V7) in prostate cancer cells.
Main Results:
- ER TRACERs suppressed ER activity and downregulated target genes in breast cancer cells, dependent on MBD2 and HDACs.
- AR TRACERs repressed both full-length AR and AR-V7, inhibiting >90% of AR-dependent transcription in prostate cancer.
- TRACERs demonstrated locus-specific gene repression and epigenetic reprogramming.
Conclusions:
- TRACERs represent a generalizable modality for pharmacologically silencing transcription factors.
- This approach offers a powerful strategy for treating cancers resistant to current therapies.
- Targeted epigenetic reprogramming via TRACERs opens new avenues in cancer treatment.
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