Differential expression of human histone deacetylase mRNAs in response to immune cell apoptosis induction by trichostatin A and butyrate.
The reversible acetylation of histones by histone deacetylases (HDACs) and acetyltransferases (HATs) plays a fundamental role in gene transcription. We previously showed that HDAC mRNA is upregulated in immune cells upon PHA-induced activation. Little is known, however, about the differential regulation of HDAC mRNAs by the HDAC inhibitors Trichostatin A (TSA) and butyrate, agents known to block proliferation and induce apoptosis. We report that apoptosis-inducing concentrations of TSA and butyrate upregulate the expression of HDAC mRNAs in a differential manner and act synergistically with PHA to induce HDAC expression, suggesting the presence of independent HDAC regulatory mechanisms. Moreover, we show that HDAC inhibitor-induced apoptosis is associated with early abrogation of gamma-IFN production by Th1 lymphocytes and with p53 mRNA downregulation. Our findings highlight the dynamic interplay of cell cycle-, activation- and apoptosis-related proteins in association with time-dependent expression of HDACs and are suggestive of different specific roles for these enzymes.
Dangond
F
F
Department of Neurology, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusettes 02115, USA. dangond@cnd.bwh.harvard.edu
Gullans
S R
SR
D000123:Acetyltransferases / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D013936:Thymidine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D002087:Butyrates; D006877:Hydroxamic Acids; D007527:Isoenzymes; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D020148:Butyric Acid; C012589:trichostatin A; D007371:Interferon-gamma; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D013936:Thymidine