Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A

Archives of Toxicology
Elisabeth LimbeckAngela Mally

Abstract

Ochratoxin A (OTA) is a potent renal carcinogen but its mechanism has not been fully resolved. In vitro and in vivo gene expression studies consistently revealed down-regulation of gene expression as the predominant transcriptional response to OTA. Based on the importance of specific histone acetylation marks in regulating gene transcription and our recent finding that OTA inhibits histone acetyltransferases (HATs), leading to loss of acetylation of histones and non-histone proteins, we hypothesized that OTA-mediated repression of gene expression may be causally linked to HAT inhibition and loss of histone acetylation. In this study, we used a novel mass spectrometry approach employing chemical 13C-acetylation of unmodified lysine residues for quantification of post-translational acetylation sites to identify site-specific alterations in histone acetylation in human kidney epithelial cells (HK-2) exposed to OTA. These results showed OTA-mediated hypoacetylation at almost all lysine residues of core histones, including loss of acetylation at H3K9 and H3K14, which are hallmarks of gene activation. ChIP-qPCR used to establish a possible link between H3K9 or H3K14 hypoacetylation and OTA-mediated down-regulation of selected genes (...Continue Reading

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Citations

Jul 18, 2019·Epigenetics : Official Journal of the DNA Methylation Society·Boyang ZhangWentao Xu
Oct 3, 2018·Toxicologic Pathology·Gordon C Hard
May 8, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Liye ZhuWentao Xu

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Methods Mentioned

BETA
acetylation
chromosomal aberrations
histone acetylation
immunoprecipitation
PCR
ChIP
Assay
ChIP-Seq
histone
transcription

Software Mentioned

MACS2
LightCycler Relative quantification
Genomatix
DAVID
Harmonizome
edgeR
deseq

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