Suicidal differential housekeeping gene activity in apoptosis induced by DCNP

Previous suggestions of CpG-specific apoptotic commitment implied critical epigenetic modulation of house-keeping genes which have canonical CpG islan ds at 5' promoter regions. Differential housekeeping gene activity however has not been shown. Using a focussed microarray (genechip) of 22 housekeepi ng genes we show this in apoptosis induced in human Chang liver cells by DC NP (2,6-dichloro-4-nitrophenol), a non-genotoxic inhibitor of sulfate detox ification. 3-7 folds downregulation of 9 genes in glycolysis, tricarboxylic acid cycle and the respiratory electron transport chain suggested gene-dir ected energy depletion which was correlated with observed ATP depletion. 4 folds downregulation of the pyruvate dehydrogenease gene suggested gene-dir ected metabolic acidosis which was correlated with observed cell acidificat ion. Other differential housekeeping gene activity, including 4 folds upreg ulation of microtubular alpha-tubulin gene, and 2 folds upregulation of ubi quitin, also had a bearing on apoptosis. Broadspectrum zVAD-fmk caspase inh ibition abolished 200 bp DNA ladder fragmentations but not the CpG-specific megabase fragmentations and other hallmarks of cell destruction, suggestin g a caspase-independent cell death. Death appeared committed at gene-level.