A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation

• DOI: 10.1371/journal.pgen.1010376
• Publication Date: 2022-08-22T17:40:36Z
• Authors: Lena Hess; Verena Moos; Arnel A. Lauber; Wolfgang Reiter; Michael Schuster; Natascha Hartl; Daniel Lackner; Thorina Boenke; Anna Koren; Paloma M. Guzzardo; Brigitte Gundacker; Anna Riegler; Petra Vician; Claudia Miccolo; Susanna Leiter; Mahesh B. Chandra...; Terezia Vcelkova; Andrea Tanzer; Jun Qi Jun; James Bradner; Gerald Brosch; Markus Hartl; Christoph Bock; Tilmann Bürckstümmer; Stefan Kubicek; Susanna Chiocca; Srividya Bhaskara; Christian Seiser
• Keywords: Histone deacetylase 2; HDAC1; HDAC3; HDAC11; Histone deacetylase 5; HDAC10; PCAF

The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- class-specific HDAC inhibitors available, these drugs do not allow a comprehensive understanding individual function, or the therapeutic potential isoform-specific targeting. To systematically compare impact catalytic functions HDAC1, HDAC2 HDAC3, we generated human HAP1 lines expressing catalytically inactive enzymes. Using this genetic toolbox effect inhibition with effects specific on viability, protein acetylation gene expression. Individual inactivation HDAC1 has only mild while HDAC3 loss results DNA damage apoptosis. Inactivation HDAC1/HDAC2 led to increased components COREST co-repressor complex, reduced deacetylase activity associated complex derepression neuronal genes. controls nuclear hormone receptor proteins expression regulated Acetylation acetyltransferases HDACs is sensitive HDAC1/HDAC2. Over wide range assays, determined that particular mimics inhibitors. Importantly, further demonstrate sensitizes cells cancer drugs. In summary, our systematic study revealed roles HDAC1/2/3 functions. We suggest targeted isoforms effectively pharmacological allowing identification relevant as targets for intervention.