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De-differentiation by Adenovirus E1A Due to Inactivation of Hippo Pathway Effectors YAP and TAZ [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130136 | GEO | 2019/06/01

REPOSITORIES: GEO

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De-differentiation by Adenovirus E1A Due to Inactivation of Hippo Pathway Effectors YAP and TAZ [ChIP-seq]

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.

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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 transcriptome by mRNA sequencing before and after infection by adenoviral e1a expressing vectors in growth arrested IMR90

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Expression profiles and ChIP on chip genomewide experiments with dl1500 virus (expressing WT small e1a).

Project description:Adenovirus e1a induces quiescent human cells to divide. We found that e1a causes global relocalization of the RB-proteins (RB, p130, p107) and p300/CBP histone acetyltransferases on promoters that restricts H3K18ac to a limited set of genes to stimulate cell cycling and inhibit antiviral responses and cellular differentiation. Soon after expression, e1a binds transiently to cell cycle/growth genes, causing enrichment of p300/CBP, PCAF, H3K18ac, depletion of RB-proteins, and transcriptional activation. e1a also associates transiently with antiviral genes, causing enrichment for RB, p130, H4K16ac, increased nucleosome density, and repression. At later times, e1a and p107 bind mainly to development/differentiation genes, repressing transcription. The temporal order of e1a binding required its interactions with p300/CBP and RB-proteins. Our data uncover a defined transcriptional and epigenetic reprogramming leading to cellular transformation. Expression profiles and ChIP on chip genomewide experiments with dl1500 virus (expressing WT small e1a).

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