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A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific ta...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436093/ https://www.ncbi.nlm.nih.gov/pubmed/35994477 http://dx.doi.org/10.1371/journal.pgen.1010376 |
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author | Hess, Lena Moos, Verena Lauber, Arnel A. Reiter, Wolfgang Schuster, Michael Hartl, Natascha Lackner, Daniel Boenke, Thorina Koren, Anna Guzzardo, Paloma M. Gundacker, Brigitte Riegler, Anna Vician, Petra Miccolo, Claudia Leiter, Susanna Chandrasekharan, Mahesh B. Vcelkova, Terezia Tanzer, Andrea Jun, Jun Qi Bradner, James Brosch, Gerald Hartl, Markus Bock, Christoph Bürckstümmer, Tilmann Kubicek, Stefan Chiocca, Susanna Bhaskara, Srividya Seiser, Christian |
author_facet | Hess, Lena Moos, Verena Lauber, Arnel A. Reiter, Wolfgang Schuster, Michael Hartl, Natascha Lackner, Daniel Boenke, Thorina Koren, Anna Guzzardo, Paloma M. Gundacker, Brigitte Riegler, Anna Vician, Petra Miccolo, Claudia Leiter, Susanna Chandrasekharan, Mahesh B. Vcelkova, Terezia Tanzer, Andrea Jun, Jun Qi Bradner, James Brosch, Gerald Hartl, Markus Bock, Christoph Bürckstümmer, Tilmann Kubicek, Stefan Chiocca, Susanna Bhaskara, Srividya Seiser, Christian |
author_sort | Hess, Lena |
collection | PubMed |
description | The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention. |
format | Online Article Text |
id | pubmed-9436093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94360932022-09-02 A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation Hess, Lena Moos, Verena Lauber, Arnel A. Reiter, Wolfgang Schuster, Michael Hartl, Natascha Lackner, Daniel Boenke, Thorina Koren, Anna Guzzardo, Paloma M. Gundacker, Brigitte Riegler, Anna Vician, Petra Miccolo, Claudia Leiter, Susanna Chandrasekharan, Mahesh B. Vcelkova, Terezia Tanzer, Andrea Jun, Jun Qi Bradner, James Brosch, Gerald Hartl, Markus Bock, Christoph Bürckstümmer, Tilmann Kubicek, Stefan Chiocca, Susanna Bhaskara, Srividya Seiser, Christian PLoS Genet Research Article The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention. Public Library of Science 2022-08-22 /pmc/articles/PMC9436093/ /pubmed/35994477 http://dx.doi.org/10.1371/journal.pgen.1010376 Text en © 2022 Hess et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hess, Lena Moos, Verena Lauber, Arnel A. Reiter, Wolfgang Schuster, Michael Hartl, Natascha Lackner, Daniel Boenke, Thorina Koren, Anna Guzzardo, Paloma M. Gundacker, Brigitte Riegler, Anna Vician, Petra Miccolo, Claudia Leiter, Susanna Chandrasekharan, Mahesh B. Vcelkova, Terezia Tanzer, Andrea Jun, Jun Qi Bradner, James Brosch, Gerald Hartl, Markus Bock, Christoph Bürckstümmer, Tilmann Kubicek, Stefan Chiocca, Susanna Bhaskara, Srividya Seiser, Christian A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation |
title | A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation |
title_full | A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation |
title_fullStr | A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation |
title_full_unstemmed | A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation |
title_short | A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation |
title_sort | toolbox for class i hdacs reveals isoform specific roles in gene regulation and protein acetylation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436093/ https://www.ncbi.nlm.nih.gov/pubmed/35994477 http://dx.doi.org/10.1371/journal.pgen.1010376 |
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