Reciprocal epigenetic modification of histone H2B occurs in chromatin during apoptosis in vitro and in vivo.
Histone H2B phosphorylation at Serine 14 (phosS14) has been proposed as an epigenetic marker of apoptotic cells, whereas acetylation at the adjacent Lysine 15 (acK15) is a property of non-dying cells. We investigated the relationship and the potential regulatory mechanisms between these two epigenetic histone modifications and internucleosomal DNA degradation during apoptosis. Using rat primary thymocytes induced to undergo apoptosis with glucocorticoids we found that H2B phosphorylated at Ser14 was associated with soluble, cleaved DNA in apoptotic nuclei. In contrast acK15 was prevalent in non-apoptotic nuclei and scarce in apoptotic nuclei. This switch between K15 acetylation and S14 phosphorylation on H2B was also observed in apoptotic thymocytes from animals treated in vivo with glucocorticoids and in a rat hepatoma cell line (HTC) induced to die by UV-C or Fas ligand. It is interesting to note that the combined use of a histone deacetylase inhibitor and glucocorticoid suppressed both S14 phosphorylation and internucleosomal DNA degradation without inhibiting apoptosis in thymocytes. Using synthetic peptides and a PKC phosphorylation assay system, we show that the deacetylation of K15 was necessary to allow the S14 phosphorylation. These findings suggest that selective chromatin post-translational modifications are associated with DNA degradation during apoptosis.
Ajiro
K
K
Laboratory of Signal Transduction, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Scoltock
A B
AB
Smith
L K
LK
Ashasima
M
M
Cidlowski
J A
JA
D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002843:Chromatin / Q000201:enzymology*; D003907:Dexamethasone / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013950:Thymus Gland / Q000737:chemistry / Q000166:cytology / Q000187:drug effects
D002843:Chromatin; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010455:Peptides; D010768:Phosphoserine; C012589:trichostatin A; D003907:Dexamethasone