Dataset Information

Regulation of cellular proteome and acetylome by catalytic and non-catalytic functions of class I histone deacetylases

ABSTRACT: Project description: Taking advantage of a newly generated model system, we examined the influence of class I HDAC catalytic and non-catalytic function on the cellular proteome and acetylome. Therefore, we generated HAP1 cell lines either lacking individual class I HDACs or expressing catalytically inactive isoforms. Using these cell lines, we investigated whether deletion or inactivation of specific class I HDACs better mimics inhibitor treated cells using isobaric labeling (TMTpro).

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Haploid Cell

SUBMITTER: Markus Hartl

LAB HEAD: Christian Seiser

PROVIDER: PXD030164 | Pride | 2022-08-16

REPOSITORIES: Pride

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Publications

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

Hess Lena L Moos Verena V Lauber Arnel A AA Reiter Wolfgang W Schuster Michael M Hartl Natascha N Lackner Daniel D Boenke Thorina T Koren Anna A Guzzardo Paloma M PM Gundacker Brigitte B Riegler Anna A Vician Petra P Miccolo Claudia C Leiter Susanna S Chandrasekharan Mahesh B MB Vcelkova Terezia T Tanzer Andrea A Jun Jun Qi JQ Bradner James J Brosch Gerald G Hartl Markus M Bock Christoph C Bürckstümmer Tilmann T Kubicek Stefan S Chiocca Susanna S Bhaskara Srividya S Seiser Christian C

PLoS genetics 20220822 8

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 ...[more]

PMID: 35994477

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Project description:Histone deacetylase 1 and 2 (HDAC1/2) are the core catalytic components of co-repressor complexes which modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an embryonic stem cell (ES) line in which Hdac1 and Hdac2 can be inactivated simultaneously using a Tamoxifen inducible CreER fusion. Loss of HDAC1/2 results in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is cell cycle dependent, since differentiated, non-proliferating cells, retain their viability. Furthermore, we observe increased mitotic defects, lagging chromosomes and micronuclei, suggesting HDAC1/2 maintain chromosomal stability. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2 deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog and Rex1. HDAC1/2 activity is regulated through binding of inositol tetraphosphate molecule [Ins(1,4,5,6)P4] (IP4) sandwiched between the HDAC and its cognate co-repressor. This raises the important question of whether the IP4 actually regulates the activity of the complex in cells. By rescuing the viability of DKO cells, we demonstrate for the first time that mutations which abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have a generic, but essential role in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors. Comparative gene expression profiles of wild type (Day 0) were compared to Hdac1lox/lox, Hdac2lox/lox; CreER ES cells on days 1, 2 and 3 following for OHT treatment using the Illumina mouseWG-6 v2 expression BeadChip platform. wild type (Day 0) were compared to Hdac1lox/lox, Hdac2lox/lox; CreER ES cells on days 1, 2 and 3 following for OHT treatment. Four time points were analyzed in triplicate.

Dataset Information

Regulation of cellular proteome and acetylome by catalytic and non-catalytic functions of class I histone deacetylases

Publications

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

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