Involvement of histone hyperacetylation in triggering DNA fragmentation of rat thymocytes undergoing apoptosis.
The treatment of rat thymocytes with trichostatin A and sodium butyrate, which are inhibitors of histone deacetylase, resulted in an increase in DNA fragmentation in a concentration-dependent manner. A significant increase in DNA fragmentation induced by these compounds was observed after a lag time of 2 h. Analysis of the fragmented DNA revealed the production of approximately 50 kb DNA fragments and DNA ladders, the biochemical hallmarks of apoptotic cell death. Judging from a laser scanning microscopic analysis, the inhibitors of histone deacetylase induced nuclear condensation, the morphological feature of apoptosis. Biochemical and morphological analyses demonstrated that trichostatin A and sodium butyrate induced thymocyte apoptosis. Furthermore, hyperacetylation of nuclear histones was observed in thymocytes treated with the inhibitors of histone deacetylase. These effects of sodium butyrate and trichostatin A were seen 0.5 and 1 h, respectively, after incubation of the cells. These results thus indicate that hyperacetylation of nucleosomal histones precedes DNA fragmentation in thymocytes undergoing apoptosis induced by trichostatin A and sodium butyrate.
Lee
E
E
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Kobe, Japan.
Furukubo
T
T
Miyabe
T
T
Yamauchi
A
A
Kariya
K
K
D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D029701:Saccharomyces cerevisiae Proteins; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D002087:Butyrates; D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D029701:Saccharomyces cerevisiae Proteins; D020148:Butyric Acid; C012589:trichostatin A; D004247:DNA; D000123:Acetyltransferases; D051548:Histone Acetyltransferases