Adenovirus E1A Activation Domain Regulates H3 Acetylation Affecting Varied Steps in Transcription at Different Viral Promoters
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116772 | GEO | 2018/07/10
REPOSITORIES: GEO
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Project description:How histone acetylation promotes transcription is not clearly understood. Here, we confirm an interaction between p300 and the adenovirus 2 large E1A activation domain (AD) and map the interacting regions in E1A by observing colocalization at an integrated lacO array of fusions of LacI-mCherry to E1A fragments with YFP-p300. Viruses with mutations in E1A subdomains were constructed and analyzed for kinetics of early viral RNA expression and association of acetylated H3K9, K18, K27, TBP, and RNA polymerase II (Pol II) across the viral genome. The results indicate that this E1A interaction with p300 is required for H3K18 and H3K27 acetylation at the E2early, E3, and E4 promoters and is required for TBP and Pol II association with the E2early promoter. In contrast, H3K18/27 acetylation was not required for TBP and Pol II association with the E3 and E4 promoters but was required for E4 transcription at a step subsequent to Pol II preinitiation complex assembly.IMPORTANCE Despite a wealth of data associating promoter and enhancer region histone N-terminal tail lysine acetylation with transcriptional activity, there are relatively few examples of studies that establish causation between these histone posttranslational modifications and transcription. While hypoacetylation of histone H3 lysines 18 and 27 is associated with repression, the step(s) in the overall process of transcription that is blocked at a hypoacetylated promoter is not clearly established in most instances. Studies presented here confirm that the adenovirus 2 large E1A protein activation domain interacts with p300, as reported previously (P. Pelka, J. N. G. Ablack, J. Torchia, A. S. Turnell, R. J. A. Grand, J. S. Mymryk, Nucleic Acids Res 37:1095-1106, 2009, https://doi.org/10.1093/nar/gkn1057), and that the resulting acetylation of H3K18/27 affects varied steps in transcription at different viral promoters.
| S-EPMC6146688 | biostudies-literature
Project description:Adenovirus-transformed cells have a de-differentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells de-repressed ~2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSC). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers and actomyosin-dependent flattening against the substratum. E1A-induced histone hypoacetylation by p300/CBP at H3K27/18 was reversed. Most of the increase in H3K27/18ac was near TEAD transcription factors associated with their co-activators YAP and TAZ regulated by the Hippo pathway. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO-family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then super-enhancers. Consistent results were also observed in rat embryo kidney cells, human fibroblasts and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental check-point controlled by signaling from the actin cytoskeleton that prevents differentiation of a progenitor cell until it is in the correct cellular and tissue environment.
2019-06-01 | GSE130133 | GEO
Project description:Adenovirus-transformed cells have a de-differentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells de-repressed ~2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSC). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers and actomyosin-dependent flattening against the substratum. E1A-induced histone hypoacetylation by p300/CBP at H3K27/18 was reversed. Most of the increase in H3K27/18ac was near TEAD transcription factors associated with their co-activators YAP and TAZ regulated by the Hippo pathway. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO-family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then super-enhancers. Consistent results were also observed in rat embryo kidney cells, human fibroblasts and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental check-point controlled by signaling from the actin cytoskeleton that prevents differentiation of a progenitor cell until it is in the correct cellular and tissue environment.
2019-06-01 | GSE130136 | GEO
Project description:Adenovirus-transformed cells have a de-differentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells de-repressed ~2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSC). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers and actomyosin-dependent flattening against the substratum. E1A-induced histone hypoacetylation by p300/CBP at H3K27/18 was reversed. Most of the increase in H3K27/18ac was near TEAD transcription factors associated with their co-activators YAP and TAZ regulated by the Hippo pathway. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO-family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then super-enhancers. Consistent results were also observed in rat embryo kidney cells, human fibroblasts and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental check-point controlled by signaling from the actin cytoskeleton that prevents differentiation of a progenitor cell until it is in the correct cellular and tissue environment.
2019-06-01 | GSE130135 | GEO
Project description:Human adenovirus type 5 oncogene E1A was shown to induce massive re-replication of cellular DNA in late S phase. Using DNA combing analysis, it was shown that DNA replication dynamics including replicon length, fork velocity and inter-origin distance were dramatically altered in E1A expressing cells as compared to that of normal serum stimulated cells. It was also shown that c-Myc that is induced in E1A expressing cells is essential for the efficient entry of E1A expressing cells into S phase.
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Project description:Identification of novel cellular binding partners of human Arglu1 and human adenovirus B7 E1A.
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Project description:Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with P300/CBP and RB proteins. To understand why, experiments with structure-based e1a mutants were analyzed with RNA- and ChIP-seq. The results indicate that e1a displaces RBs from E2F activation domains and, by promoting P300 acetylation of RB1 K873/K874, locks them into a repressing conformation that interacts with repressive chromatin modifying enzymes. e1a then delivers these repressing p300-e1a-RB1 complexes to cell genes that have unusually high P300 association with the gene body, enriched in genes of the TGFb-, TNF-, and IL1-signaling pathways. The P300-e1a-RB complex condenses chromatin, dependent on HDAC activity, P300 lysine acetylase activity, the P300 bromodomain, and acetylation of RB K873/K874 and e1a K239, contributing to repression of host genes that would otherwise inhibit cell cycling. The data suggest why e1a must bind P300/CBP as well as RBs for oncogenic transformation and why a trimeric P300-e1a-RB1 complex is required. Examination of RB1 rearrangements by adenoviral e1a in IMR90
2014-08-15 | E-GEOD-59689 | biostudies-arrayexpress
Project description:Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with P300/CBP and RB proteins. To understand why, experiments with structure-based e1a mutants were analyzed with RNA- and ChIP-seq. The results indicate that e1a displaces RBs from E2F activation domains and, by promoting P300 acetylation of RB1 K873/K874, locks them into a repressing conformation that interacts with repressive chromatin modifying enzymes. e1a then delivers these repressing p300-e1a-RB1 complexes to cell genes that have unusually high P300 association with the gene body, enriched in genes of the TGFb-, TNF-, and IL1-signaling pathways. The P300-e1a-RB complex condenses chromatin, dependent on HDAC activity, P300 lysine acetylase activity, the P300 bromodomain, and acetylation of RB K873/K874 and e1a K239, contributing to repression of host genes that would otherwise inhibit cell cycling. The data suggest why e1a must bind P300/CBP as well as RBs for oncogenic transformation and why a trimeric P300-e1a-RB1 complex is required. Examination of POL II rearrangements by adenoviral e1a in IMR90
2014-08-15 | E-GEOD-59691 | biostudies-arrayexpress
Project description:Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with P300/CBP and RB proteins. To understand why, experiments with structure-based e1a mutants were analyzed with RNA- and ChIP-seq. The results indicate that e1a displaces RBs from E2F activation domains and, by promoting P300 acetylation of RB1 K873/K874, locks them into a repressing conformation that interacts with repressive chromatin modifying enzymes. e1a then delivers these repressing p300-e1a-RB1 complexes to cell genes that have unusually high P300 association with the gene body, enriched in genes of the TGFb-, TNF-, and IL1-signaling pathways. The P300-e1a-RB complex condenses chromatin, dependent on HDAC activity, P300 lysine acetylase activity, the P300 bromodomain, and acetylation of RB K873/K874 and e1a K239, contributing to repression of host genes that would otherwise inhibit cell cycling. The data suggest why e1a must bind P300/CBP as well as RBs for oncogenic transformation and why a trimeric P300-e1a-RB1 complex is required. Examination of RB1 rearrangements by adenoviral e1a as well as mutant e1as in IMR90
2014-08-15 | E-GEOD-59690 | biostudies-arrayexpress
Project description:Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with P300/CBP and RB proteins. To understand why, experiments with structure-based e1a mutants were analyzed with RNA- and ChIP-seq. The results indicate that e1a displaces RBs from E2F activation domains and, by promoting P300 acetylation of RB1 K873/K874, locks them into a repressing conformation that interacts with repressive chromatin modifying enzymes. e1a then delivers these repressing p300-e1a-RB1 complexes to cell genes that have unusually high P300 association with the gene body, enriched in genes of the TGFb-, TNF-, and IL1-signaling pathways. The P300-e1a-RB complex condenses chromatin, dependent on HDAC activity, P300 lysine acetylase activity, the P300 bromodomain, and acetylation of RB K873/K874 and e1a K239, contributing to repression of host genes that would otherwise inhibit cell cycling. The data suggest why e1a must bind P300/CBP as well as RBs for oncogenic transformation and why a trimeric P300-e1a-RB1 complex is required. Chromatin IP background Input DNA for ChIP-seq normalization
2014-08-15 | E-GEOD-59692 | biostudies-arrayexpress