High throughput screening identifies modulators of histone deacetylase inhibitors

Authors

Ann-Christin Gaupel, University at Albany, State University of New York
Thomas Begley, University at Albany, State University of New York
Martin Tenniswood, University at Albany, State University of New York

Preview

Document Type

Article

Publication Date

6-26-2014

DOI

https://doi.org/10.1186/1471-2164-15-528

Abstract

Background

Previous studies from our laboratory and others have demonstrated that in addition to altering chromatin acetylation and conformation, histone deacetylase inhibitors (HDACi) disrupt the acetylation status of numerous transcription factors and other proteins. A whole genome yeast deletion library screen was used to identify components of the transcriptional apparatus that modulate the sensitivity to the hydroxamic acid-based HDACi, CG-1521.

Results

Screening 4852 haploid Saccharomyces cerevisiae deletion strains for sensitivity to CG-1521 identifies 407 sensitive and 80 resistant strains. Gene ontology (GO) enrichment analysis shows that strains sensitive to CG-1521 are highly enriched in processes regulating chromatin remodeling and transcription as well as other ontologies, including vacuolar acidification and vesicle-mediated transport. CG-1521-resistant strains include those deficient in the regulation of transcription and tRNA modification. Components of the SAGA histone acetyltransferase (HAT) complex are overrepresented in the sensitive strains, including the catalytic subunit, Gcn5. Cell cycle analysis indicates that both the wild-type and gcn5Δ strains show a G₁ delay after CG-1521 treatment, however the gcn5Δ strain displays increased sensitivity to CG-1521-induced cell death compared to the wild-type strain. To test whether the enzymatic activity of Gcn5 is necessary in the response to CG-1521, growth assays with a yeast strain expressing a catalytically inactive variant of the Gcn5 protein were performed and the results show that this strain is less sensitive to CG-1521 than the gcn5Δ strain.

Conclusion

Genome-wide deletion mutant screening identifies biological processes that affect the sensitivity to the HDAC inhibitor CG-1521, including transcription and chromatin remodeling. This study illuminates the pathways involved in the response to CG-1521 in yeast and provides incentives to understand the mechanisms of HDAC inhibitors in cancer cells. The data presented here demonstrate that components of the SAGA complex are involved in mediating the response to CG-1521. Additional experiments suggest that functions other than the acetyltransferase activity of Gcn5 may be sufficient to attenuate the effects of CG-1521 on cell growth.

Comments

This is the Publisher’s PDF of the following article made available by BMC Genomics: Gaupel, AC., Begley, T. & Tenniswood, M. High throughput screening identifies modulators of histone deacetylase inhibitors. BMC Genomics 15, 528 (2014). https://doi.org/10.1186/1471-2164-15-528

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Gaupel, Ann-Christin; Begley, Thomas; and Tenniswood, Martin, "High throughput screening identifies modulators of histone deacetylase inhibitors" (2014). Biological Sciences Faculty Scholarship. 33.
https://scholarsarchive.library.albany.edu/biology_fac_scholar/33