Integrated HPV18 acts as enhancer-like RNA and form phase-separated condensates to promote oncogenic genes expression.
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ABSTRACT:
PROVIDER: PRJNA1051147 | ENA |
REPOSITORIES: ENA
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Project description:Most of the cervical cancers are caused by human papillomavirus (HPV) infection. It has been known that, in HeLa cells, HPV18 viral genome is integrated at chromosome 8q24.21 and activates transcription of proto-oncogene c-Myc. However, the mechanism of how the integrated HPV fragment exhibits transcription activation function has not been fully elucidated. In this study, we found that HPV18 transcripts themselves have an enhancer RNA-like function to activate their proximal genes including CCAT1-5L and c-Myc. We showed that the human genome-integrated HPV18 genes are activated by transcription coregulators BRD4, Mediator. The transcribed HPV18 RNAs form a liquid-like condensate at chromosome 8q24.21 locus, which in turn accumulates RNA polymerase II. Moreover, we identified uncharacterized transcript from Upstream Region of CCAT1-5L, named URC. The URC RNA is transcribed as a chimera RNA with HPV18 and is composed of 3'-untranslated region of HPV18 transcript. We found that the URC contributes to stabilization of HPV18 RNAs by supplying a poly-adenylation site for HPV18 transcript. Our findings suggest that HPV18 integration at 8q24.21 locus causes HPV18-URC chimera RNA and promotes tumorigenesis through RNA-based liquid droplet formation.
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Project description:lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation
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Project description:lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation
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Project description:Gene programs that control differentiation are regulated through the interplay between DNA, RNA, and protein. Cooperation among these fundamental cellular components can occur through highly structured interactions connecting domains formed by specific sequences of nucleotides, ribonucleotides, and/or amino acids and also through the assembly of biomolecular condensates. Here, we show that endoderm differentiation is regulated through the interaction of the long noncoding (lnc) RNA DIGITand the bromodomain and extra-terminal (BET) domain family protein BRD3. BRD3 forms phase-separated condensates that contain DIGIT, occupies enhancers of endoderm transcription factors, and is required for endoderm differentiation. Purified BRD3 binds to acetylated histone H3 lysine 18 (H3K18ac) in vitro and occupies regions of the genome enriched in H3K18ac during endoderm differentiation, including the key transcription factors that regulate endoderm differentiation. DIGIT is also enriched in regions of H3K18ac, and depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings support a model where cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest a broader role for protein-lncRNA phase-separated condensates as regulators of transcription in development.
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Project description:lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation [RIP-seq]
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Project description:The gene expression programs that define each cell’s identity are controlled by master transcription factors (TFs) that bind cell-type specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here we present evidence that signaling factors for the WNT, TGF-β and JAK/STAT pathways employ their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA binding factors to selectively occupy super-enhancer associated genes. We propose that the cell-type specificity of the response to signaling is mediated, in part, by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.
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Project description:Proteins and RNA are able to phase separate from the aqueous cellular environment to form sub-cellular compartments called condensates. This process results in a protein-RNA mixture that is chemically distinct from the surrounding aqueous phase. Here we use mass spectrometry to characterize the metabolomes of condensates. To test this, we prepared mixtures of phase-separated proteins and cellular metabolites and identified metabolites enriched in the condensate phase. These proteins included SARS-CoV-2 nucleocapsid, as well as low complexity domains of MED1 and HNRNPA1.
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Project description:Proteins and RNA are able to phase separate from the aqueous cellular environment to form sub-cellular compartments called condensates. This process results in a protein-RNA mixture that is chemically distinct from the surrounding aqueous phase. Here we use mass spectrometry to characterize the metabolomes of condensates. To test this, we prepared mixtures of phase-separated proteins and cellular metabolites and identified metabolites enriched in the condensate phase. These proteins included SARS-CoV-2 nucleocapsid, as well as low complexity domains of MED1 and HNRNPA1.
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