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Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [FAIRE-Seq]

ABSTRACT: Topoisomerases are essential for resolving topological problems in the genome, while their function in gene regulation, especially during cellular differentiation, remains unknown. We reveal that the expression of two Topo II isoforms, Top2a and Top2ß, is characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, Top2a preferentially binds to promoters embedded in an active chromatin environment. Inhibition of Top2a activity results in misregulation of target gene expression that accompanies accumulation of double-strand breaks. Common targets of Top2a and Top2ß are housekeeping genes while their unique targets are involved in proliferation/pluripotency and neurogenesis, respectively. Moreover, a subset of Top2a targets exhibit bivalent chromatin state that is resolved upon differentiation concomitant with their activation and occupancy by Top2ß, a feature further observed for long genes. These findings suggest that Top2a not only contributes to stem cell transcriptome regulation but may also prime developmental genes for subsequent activation upon differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE49141 | GEO | 2013/10/10

SECONDARY ACCESSION(S): PRJNA213140

REPOSITORIES: GEO

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Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [RNA-Seq]

Project description:Topoisomerases are essential for resolving topological problems in the genome, while their function in gene regulation, especially during cellular differentiation, remains unknown. We reveal that the expression of two Topo II isoforms, Top2a and Top2ß, is characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, Top2a preferentially binds to promoters embedded in an active chromatin environment. Inhibition of Top2a activity results in misregulation of target gene expression that accompanies accumulation of double-strand breaks. Common targets of Top2a and Top2ß are housekeeping genes while their unique targets are involved in proliferation/pluripotency and neurogenesis, respectively. Moreover, a subset of Top2a targets exhibit bivalent chromatin state that is resolved upon differentiation concomitant with their activation and occupancy by Top2ß, a feature further observed for long genes. These findings suggest that Top2a not only contributes to stem cell transcriptome regulation but may also prime developmental genes for subsequent activation upon differentiation. mRNA profiles of DMSO and ICRF-193 treated mESCs were generated by deep sequencing in triplicates. ICRF-193 is a well established catalytic inhibitor of Topoisomerase II, hence, we used ICRF-193 to the elucidate role of Top2a catalytic activity on transcription by genome wide transcription profiling.

2013-10-10 | E-GEOD-46066 | biostudies-arrayexpress

Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [RNA-Seq]

2013-10-10 | GSE46066 | GEO

Gene regulation and priming by Topoisomerase II? in embryonic stem cells [FAIRE-Seq]

2013-10-10 | E-GEOD-49141 | biostudies-arrayexpress

Gene regulation and priming by Topoisomerase IIα in embryonic stem cells [ChIP-chip]

Project description:Topoisomerases are essential for resolving topological problems in the genome, while their function in gene regulation, especially during cellular differentiation, remains elusive/unknown. We reveal that the expression of two Topo II isoforms, Top2α and Top2β, is characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, Top2α preferentially binds to promoters embedded in an active chromatin environment. Inhibition of Top2α activity results in misregulation of target gene expression that accompanies accumulation of double-strand breaks. Common targets of Top2α and Top2β are housekeeping genes while their unique targets are involved in proliferation/pluripotency and neurogenesis (Can we say this as this might be because we are driving neurons from ES cells), respectively. Moreover, a small subset of Top2α targets exhibit bivalent chromatin state that is resolved upon differentiation concomitant with their activation and occupancy by Top2β, a feature further observed for large lengthlong genes. These findings suggest that Top2α not only contributes to stem cell transcriptome regulation but may also prime developmental genes for subsequent activation by Top2β.

2013-10-10 | GSE45890 | GEO

Gene regulation and priming by Topoisomerase IIÎ± in embryonic stem cells [ChIP-chip]

Project description:Topoisomerases are essential for resolving topological problems in the genome, while their function in gene regulation, especially during cellular differentiation, remains elusive/unknown. We reveal that the expression of two Topo II isoforms, Top2Î± and Top2Î², is characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, Top2Î± preferentially binds to promoters embedded in an active chromatin environment. Inhibition of Top2Î± activity results in misregulation of target gene expression that accompanies accumulation of double-strand breaks. Common targets of Top2Î± and Top2Î² are housekeeping genes while their unique targets are involved in proliferation/pluripotency and neurogenesis (Can we say this as this might be because we are driving neurons from ES cells), respectively. Moreover, a small subset of Top2Î± targets exhibit bivalent chromatin state that is resolved upon differentiation concomitant with their activation and occupancy by Top2Î², a feature further observed for large lengthlong genes. These findings suggest that Top2Î± not only contributes to stem cell transcriptome regulation but may also prime developmental genes for subsequent activation by Top2Î². Chromatin IP was performed with Top2Î± antibodies in WT ES cells and hybridized to custom designed tiling array.

2013-10-10 | E-GEOD-45890 | biostudies-arrayexpress

MYC assembles and stimulates topoisomerases 1 & 2 in a “topisome” [cross-CAD-seq]

Project description:High-intensity transcription and replication supercoil DNA to levels that can impede or halt these processes. As a potent transcription amplifier and replication accelerator, the proto-oncogene MYC must somehow manage these high levels of torsional stress. By comparing gene expression with the recruitment of topoisomerases and MYC to promoters, we surmised a direct association of MYC with Topoisomerases 1 (TOP1) and 2A (TOP2A) that was confirmed in vitro and in vivo. Beyond recruiting topoisomerases, MYC directly stimulates their activities in vitro and in vivo. We identify a MYC-nucleated “topoisome” complex that unites and increases the levels of both both TOP1 and TOP2, as well as their activities at promoters and enhancers. Whether TOP2A or TOP2B is included in the topoisome, is dictated by the presence of c-MYC or MYCN, respectively. Thus, in vivo and in vitro, MYC assembles tools that simplify DNA topology and promote genome function under high output conditions.

2021-12-09 | GSE181449 | GEO

MYC assembles and stimulates topoisomerases 1 & 2 in a “topisome” [CAD-seq]

2021-12-09 | GSE181448 | GEO

MYC assembles and stimulates topoisomerases 1 & 2 in a “topisome” [ChIP-seq]

2021-12-09 | GSE181447 | GEO

Landscape of TOP2A-mediated DNA cleavage across the human genome

Project description:Type II topoisomerases orchestrate proper DNA topology and they also are the targets of anticancer drugs that cause leukemias with balanced translocations as secondary cancers. Here, we develop a novel high-throughput sequencing technology to define TOP2 cleavage sites at single base precision in human cells and use the technology to characterize TOP2A cleavage genome-wide in the K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence predilections, occurs in cleavage cluster regions (CCRs) and is enriched in introns and lincRNA loci. In coding genes we discover a bias of TOP2A CCRs towards the distal regions of gene bodies and proximal shifts in TOP2A CCRs with TOP2 poisons. We find high TOP2A cleavage levels in the genes involved in translocations associated with TOP2 poisons in leukemia. In addition, we find that large a proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. By making comparisons to ENCODE data, we uncover distinct TOP2A CCR clusters that overlap with marks of gene transcription, open chromatin and enhancers. Our findings implicate TOP2A as the DNA damage mediator in oncogenic translocations more broadly than was previously appreciated. They also identify TOP2A as a functional DNA element that contributes to the regulation of transcription elongation and gene activation.

2017-03-08 | GSE79593 | GEO

Topo-Seq application for topoisomerases binding sites identification with a single-nucleotide resolution

Project description:Topo-Seq is a ChIP-Seq-based methodology that allows high-throughput identification of topoisomerases binding (cleavage) sites with a single-base precision. On a first stage of the project DNA-gyrase binding sites on a Escherichia coli DY330 genome are investigated.

2018-07-17 | GSE117186 | GEO

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