Study of Topoisomerase I in human
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57628 | GEO | 2016/04/12
REPOSITORIES: GEO
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Project description:RNA polymerase II (RNAPII) pausing release is a recently recognized checkpoint for transcriptional regulation. The biological roles of RNAPII pausing release and the mechanisms that by which extracellular signals control it are incompletely understood. Here we identify a novel mechanism by which VEGF stimulates RNAPII pausing-release through acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells (ECs), ETS1 uniquely bound transcribed gene promoters and stimulated their expression by broadly increasing RNA polymerase II (RNAPII) pause release. VEGF enhanced ETS1 chromatin occupancy. Furthermore, VEGF increased ETS1 acetylation, enhancing its binding by BRD4 and thereby stimulating RNAPII pause release. This ETS1-mediated transduction of VEGF signaling to increase RNAPII pausing release was essential for EC angiogenic responses in vitro and in vivo. Together, our results define a new angiogenic pathway in which VEGF enhances ETS1-Brd4 interaction to broadly promote RNAPII pause release and drive angiogenesis.
2016-12-31 | GSE93030 | GEO
Project description:Distal enhancers characterized by H3K4me1 mark play critical roles in developmental and transcriptional programs. However, potential roles of specific distal regulatory elements in regulating RNA Polymerase II (Pol II) promoter-proximal pause release remain poorly investigated. Here we report that a unique cohort of jumonji C domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) co-bound distal enhancers, termed anti-pause enhancers (A-PEs), regulate promoter-proximal pause release of a large subset of transcription units via long-range interactions. Brd4-dependent JMJD6 recruitment on A-PEs mediates erasure of H4R3me2(s), which is directly read by 7SK snRNA, and decapping/demethylation of 7SK snRNA, ensuring the dismissal of the 7SKsnRNA/HEXIM inhibitory complex. The interactions of both JMJD6 and Brd4 with the P-TEFb complex permit its activation and pause release of regulated coding genes. The functions of JMJD6/ Brd4-associated dual histone and RNA demethylase activity on anti-pause enhancers have intriguing implications for these proteins in development, homeostasis and disease. All Gro-seq(s) were designed to reveal the transcriptional targets of JMJD6 and Brd4, and assess the role of JMJD6 and Brd4 in Pol II promoter-proximal pause release. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of the anti-pause enhancers (A-PEs) discovered in the current study.
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Project description:Transcription inhibition has become an attractive strategy for anticancer therapy because many cancers arise from dysregulated transcription programs. Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) coordinate each other to regulate transcriptional elongation. Using a collection of patient-derived xenograft mouse models of pancreatic cancer we show that the combined inhibition of TOP1 and BRD4 is synergistic in arresting tumor growth. We link this effect to the ability of TOP1 and BRD4 to control pause-release, a rate-limiting step in early elongation. By comparing nascent transcripts with the recruitment of elongation and termination factors along genes, we found that combined inhibition of TOP1 and BRD4, while globally impairing RNA production, also disturbs the recruitment of proteins involved in termination. Thus, RNA polymerases stay engaged with the DNA downstream of polyadenylation sites for hundreds of kilobases leading to readthrough-transcription. Because this pervasive transcription occurs also during replication, it perturbs replisome progression leading to increased DNA damage and cell cycle arrest. The synergistic effect of TOP1 and BRD4 inhibition is specific for the tumor cells as negligible transcriptional defects are observed in non-tumor cells. This work provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors in the treatment of highly transcription- and replication-driven tumors.
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Project description:Transcription inhibition has become an attractive strategy for anticancer therapy because many cancers arise from dysregulated transcription programs. Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) coordinate each other to regulate transcriptional elongation. Using a collection of patient-derived xenograft mouse models of pancreatic cancer we show that the combined inhibition of TOP1 and BRD4 is synergistic in arresting tumor growth. We link this effect to the ability of TOP1 and BRD4 to control pause-release, a rate-limiting step in early elongation. By comparing nascent transcripts with the recruitment of elongation and termination factors along genes, we found that combined inhibition of TOP1 and BRD4, while globally impairing RNA production, also disturbs the recruitment of proteins involved in termination. Thus, RNA polymerases stay engaged with the DNA downstream of polyadenylation sites for hundreds of kilobases leading to readthrough-transcription. Because this pervasive transcription occurs also during replication, it perturbs replisome progression leading to increased DNA damage and cell cycle arrest. The synergistic effect of TOP1 and BRD4 inhibition is specific for the tumor cells as negligible transcriptional defects are observed in non-tumor cells. This work provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors in the treatment of highly transcription- and replication-driven tumors.
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Project description:Transcription inhibition has become an attractive strategy for anticancer therapy because many cancers arise from dysregulated transcription programs. Topoisomerase 1 (TOP1) and bromodomain containing protein 4 (BRD4) coordinate each other to regulate transcriptional elongation. Using a collection of patient-derived xenograft mouse models of pancreatic cancer we show that the combined inhibition of TOP1 and BRD4 is synergistic in arresting tumor growth. We link this effect to the ability of TOP1 and BRD4 to control pause-release, a rate-limiting step in early elongation. By comparing nascent transcripts with the recruitment of elongation and termination factors along genes, we found that combined inhibition of TOP1 and BRD4, while globally impairing RNA production, also disturbs the recruitment of proteins involved in termination. Thus, RNA polymerases stay engaged with the DNA downstream of polyadenylation sites for hundreds of kilobases leading to readthrough-transcription. Because this pervasive transcription occurs also during replication, it perturbs replisome progression leading to increased DNA damage and cell cycle arrest. The synergistic effect of TOP1 and BRD4 inhibition is specific for the tumor cells as negligible transcriptional defects are observed in non-tumor cells. This work provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors in the treatment of highly transcription- and replication-driven tumors.
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Project description:P-TEFb, a heterodimer of kinase, CDK9, and Cyclin T1, is a critical regulator of promoter-proximal pause release of Pol II in metazoans. It is capable of forming three larger multiprotein complexes, including the super elongation complex (SEC), the BRD4/P-TEFb complex and the 7SK snRNP. In the SEC or the BRD4/P-TEFb, P-TEFb is enzymatically active, while in the 7SK snRNP, its activity is inhibited. The SEC consists of AFF1 or 4, ENL or AF9, ELL1, 2 or 3 and EAF1 or 2 in addition to P-TEFb, the only subunit with catalytic activity, and the noncatalytic subunits have been found to be able to regulate pause release through P-TEFb. One recent study showed that in human DLD-1 cells, the SEC only regulates pause release of heat shock (HS) genes, whereas the BRD4/P-TEFb complex regulates pause release of the rest of the genes. In this study, we found that AFF4 knockdown in human HEL cells decreased not only cellular level but also global chromatin occupancy of CTD serine 2 phosphorylated Pol II, and notably, increased promoter-proximal pause of Pol II on several hundred HS and thousands of non-HS genes. Mechanistically, AFF4 facilitates pause release likely by facilitating the binding of P-TEFb to Pol II. These results suggest that the extent of impact of AFF4 on pause release is likely to be context-dependent or cell-type dependent.
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