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. 2008 Aug 22;321(5892):1084-5.
doi: 10.1126/science.1155544.

Adenovirus Small e1a Alters Global Patterns of Histone Modification

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Free PMC article

Adenovirus Small e1a Alters Global Patterns of Histone Modification

Gregory A Horwitz et al. Science. .
Free PMC article

Abstract

Adenovirus small early region 1a (e1a) protein drives cells into S phase by binding RB family proteins and the closely related histone acetyl transferases p300 and CBP. The interaction with RB proteins displaces them from DNA-bound E2F transcription factors, reversing their repression of cell cycle genes. However, it has been unclear how the e1a interaction with p300 and CBP promotes passage through the cell cycle. We show that this interaction causes a threefold reduction in total cellular histone H3 lysine 18 acetylation (H3K18ac). CBP and p300 are required for acetylation at this site because their knockdown causes specific hypoacetylation at H3K18. SV40 T antigen also induces H3K18 hypoacetylation. Because global hypoacetylation at this site is observed in prostate carcinomas with poor prognosis, this suggests that processes resulting in global H3K18 hypoacetylation may be linked to oncogenic transformation.

Figures

Fig. 1
Fig. 1
e1a induces hypoacetylation of H3K18. Contact inhibited human primary IMR90 fibroblasts were mock-infected or infected with Ad5 dl1500 (e1a only). 24 hours p.i., cells were fixed and immunostained with antibodies to e1a (green), either (A) H3K9ac (red) or (B) K3K18ac (red), and 4´,6´-diamidino-2-phenylindole (DAPI) to stain nuclei. Merges of green and red signals are also shown. (C) Fold change in histone modifications after dl1500-infection of IMR90 cells determined by mass spectrometry (fig. S2). Western blots of histones from (D) IMR90 cells infected with dl312 (no e1a) or dl1500 (e1a only) and (E) HeLa cells transduced with the indicated retrovirus vectors or dl1500-infected.
Fig. 2
Fig. 2
CBP or p300 is required for acetylating H3K18. (A) Computational image analysis of immunofluorescent micrographs after IMR90 siRNA transfections against p300 and CBP (18) (fig. S7). The fraction T SD of nonstaining nuclei is plotted, n = 4. (Inset) Typical micrographs. (B) Nuclear extract from dl1500-infected HeLa cells 24 hours p.i. was subjected to three successive immunoprecipitations (IP1 to IP3) with equal amounts of monoclonal antibody (mAb) M73 against e1a. One-tenth of the total IP and supernatant (Sup1 to Sup3) after each IP were subjected to Western blotting. Differences in post-translational modifications caused e1a to appear as a doublet. (C) Twofold increasing amounts of p300/CBP IPed from mock- or dl1500-infected HeLa cells were incubated with glutathione S-transferase (GST)–H3 N terminus or hypoacetylated nucleosomes plus acetyl-coenzyme A (18), and products were assayed by Western blotting with anti-H3K18ac or anti-H3K14ac. (D) Histones from MEFs transformed with a retrovirus vector expressing SV40 large T antigen or the parental MEFs (top) and from IMR90 fibroblasts mock-infected or infected with an Ad expression vector for SV40 large T antigen 24 hours p.i. (bottom) were subjected to Western blotting.

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