Epigenetic reprogramming by adenovirus e1a

Abstract

Adenovirus e1a induces quiescent human cells to replicate. We found that e1a causes global relocalization of the RB (retinoblastoma) proteins (RB, p130, and p107) and p300/CBP histone acetyltransferases on promoters, the effect of which is to restrict the acetylation of histone 3 lysine-18 (H3K18ac) to a limited set of genes, thereby stimulating cell cycling and inhibiting antiviral responses and cellular differentiation. Soon after expression, e1a binds transiently to promoters of cell cycle and growth genes, causing enrichment of p300/CBP, PCAF (p300/CBP-associated factor), and H3K18ac; depletion of RB proteins; and transcriptional activation. e1a also associates transiently with promoters of antiviral genes, causing enrichment for RB, p130, and H4K16ac; increased nucleosome density; and transcriptional repression. At later times, e1a and p107 bind mainly to promoters of development and differentiation genes, repressing transcription. The temporal order of e1a binding requires its interactions with p300/CBP and RB proteins. Our data uncover a defined epigenetic reprogramming leading to cellular transformation.

Fig. 1

Temporally ordered pattern of e1a binding reprograms host cell gene expression profile. (A) Time course of e1a genome-wide localization in IMR90 fibroblasts. Each row represents the promoter of a gene in 500-bp intervals from -5.5 to +2.5 kb of the transcription start site (TSS). Enrichment Z scores are indicated to the right of each cluster. (B) Relative gene expression changes of the three clusters at 6, 12, and 24 hours after e1a expression (note the scale).

Fig. 2

Redistribution of transcriptional co-regulators and epigenetic reprogramming by e1a. The genome-wide distributions of p300, H3K18ac, H3K9ac, H4K16ac, histone H3, RB, p130, and p107 in the three e1a-binding clusters at the indicated times after e1a expression are shown.

Fig. 3

Temporally ordered target gene selection and proper binding by e1a requires interactions with p300/CBP and the RB proteins. (A and C) Time course of R2Ge1a and ΔCR2e1a genome-wide localization in IMR90 fibroblasts in the three WTe1a-binding clusters (Fig. 1A). Also shown are the distribution and enrichment Z scores of H3K9ac and H3K18ac in R2Ge1a- or ΔCR2e1a-infected versus mock-infected cells. (B and D) Relative expression levels of the three clusters in each mutant 24 hours after e1a expression.