The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation

Abstract

BackgroundDysregulation of the common stress responsive transcription factor ATF3 has been causally linked to many important human diseases such as cancer, atherosclerosis, infections, and hypospadias. Although it is believed that the ATF3 transcription activity is central to its cellular functions, how ATF3 regulates gene expression remains largely unknown. Here, we employed ATF3 wild-type and knockout isogenic cell lines to carry out the first comprehensive analysis of global ATF3-binding profiles in the human genome under basal and stressed (DNA damage) conditions.ResultsAlthough expressed at a low basal level, ATF3 was found to bind a large number of genomic sites that are often associated with genes involved in cellular stress responses. Interestingly, ATF3 appears to bind a large portion of genomic sites distal to transcription start sites and enriched with p300 and H3K27ac. Global gene expression profiling analysis indicates that genes proximal to these genomic sites were often regulated by ATF3. While DNA damage elicited by camptothecin dramatically altered the ATF3 binding profile, most of the genes regulated by ATF3 upon DNA damage were pre-bound by ATF3 before the stress. Moreover, we demonstrated that ATF3 was co-localized with the major stress responder p53 at genomic sites, thereby collaborating with p53 to regulate p53 target gene expression upon DNA damage.ConclusionsThese results suggest that ATF3 likely bookmarks genomic sites and interacts with other transcription regulators to control gene expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2664-8) contains supplementary material, which is available to authorized users.

Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis

“…(i) The Atf3 gene is expressed at a low basal level, but its expression is greatly increased by a wide spectrum of stress signals (28). Intriguingly, by global analysis of ATF3-binding sites using ChIP-seq, Yan and colleagues (60) showed that ATF3 binds to a surprisingly large number of sites on the genome; furthermore, their data supported the idea that ATF3 "bookmarks" sites on the genome to allow rapid transcriptional response upon stress stimulation. (ii) Atf3 is an immediate-early gene (31), which has a hallmark of encoding transcription factors that regulate the expression of other transcription factor genes, resulting in a cascade of changes in transcriptional profile.…”

“…S3D), i.e., ATF/CRE, AP-1, and closely related sites (29,60). We tested whether ATF3 binds to the Ccl2 promoter by ChIP assay and found consistent binding at the −2.3-kb site (Fig.…”

Genomic Characterization of Metformin Hepatic Response

“…Our analysis of metformin increased H3K27ac peaks showed enrichment for ATF3 binding motifs (Fig 4D). Interestingly, ATF3 was also recently shown to bind genomic sites enriched with EP300 and H3K27ac for transcriptional regulation [59]. Moreover, analysis of ATF3 marks unique to either the non-treated or metformin treated conditions were found to be overrepresented in differentially expressed H3K27ac peaks when compared to all H3K27ac peaks.…”

The sense behind retroviral anti-sense transcription

“…The consensus binding sites for transcription factors predicted to interact with these retroviral promoters have been previously described [53]. The consensus binding sites for ATF3, AhR/ARNT, COUPTF1, E2F1, ETF, ENKTF1, FOXP3, GATA family, GCF, HNF, HIF, NF-Y, RxRα, SRF, TCF-4E, and TRβ were obtained from [74–90]. Only those sites with a maximum of one base pair deviation from the consensus binding sequence (or two for large hormonal response elements) were annotated on the target retroviral 3′ LTR.…”