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Updated: Jun 19, 2026
In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing
Published on: May 5, 2023
Mtg16/Eto2 tumor suppressor maintains and establishes repression by distinct mechanisms
Anna E Gilbert1, Monica L Bomber1, Jacob D Ellis1
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Abstract:
The myeloid translocation gene (Mtg) family of transcriptional corepressors is a frequent target of chromosomal translocations and deletions in cancer, yet the mechanisms underlying tumor suppression and transcriptional repression are unclear. We employed a chemical-genetic system that enabled rapid degradation and recovery of Mtg16 to study both the maintenance and re-establishment of transcriptional repression. Nascent transcription and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses showed that Mtg16 repressed highly accessible promoters and enhancers, including Lmo2, Myb, and Gfi1b. The highest confidence targets included these oncogenes, which were transcribed at low levels in the presence of Mtg16 and re-repressed upon its recovery. Proximity ligation assays showed that HEB associated with p300 in the absence of Mtg16, but endogenous levels of Mtg16 impaired this association. Repression was associated with decreased H3K27ac, but loss of H3K27ac also occurred at non-repressed sites. Strikingly, HDAC inhibition had little effect on the maintenance of repression but strongly impaired re-repression following Mtg16 restoration, revealing a selective requirement for HDACs during repression onset.
Insights
The myeloid translocation gene 16 (Mtg16) corepressor maintains transcriptional repression of key oncogenes. Its restoration selectively requires HDACs for re-establishing repression, offering new therapeutic insights.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- The myeloid translocation gene (Mtg) family of transcriptional corepressors plays a role in tumor suppression.
- Mechanisms of Mtg-mediated transcriptional repression and tumor suppression are not fully understood.
- Chromosomal translocations frequently target Mtg genes in various cancers.
Purpose of the Study:
- To investigate the mechanisms of Mtg16-mediated transcriptional repression.
- To explore the role of Mtg16 in maintaining and re-establishing transcriptional repression.
- To elucidate the role of histone deacetylases (HDACs) in Mtg16-mediated repression.
Main Methods:
- Chemical-genetic system for rapid Mtg16 degradation and recovery.
- Nascent transcription analysis.
- Assay for transposase-accessible chromatin using sequencing (ATAC-seq).
- Proximity ligation assays.
- Histone modification analysis (H3K27ac).
Main Results:
- Mtg16 represses transcription of highly accessible promoters and enhancers, including oncogenes like Lmo2, Myb, and Gfi1b.
- Mtg16 impairs the association of HEB with p300.
- Repression by Mtg16 is associated with decreased H3K27ac.
- HDAC inhibition affects re-repression but not the maintenance of Mtg16-mediated repression.
Conclusions:
- Mtg16 functions as a transcriptional corepressor targeting key oncogenes.
- HDACs are selectively required for the re-establishment, but not the maintenance, of Mtg16-mediated repression.
- These findings provide insights into Mtg16's tumor suppressor function and potential therapeutic strategies.
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