Gene regulation and priming by Topoisomerase IIα in embryonic stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Sudhir Thakurela
PROVIDER: E-GEOD-46070 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Gene regulation and priming by topoisomerase IIα in embryonic stem cells.
Thakurela Sudhir S Garding Angela A Jung Johannes J Schübeler Dirk D Burger Lukas L Tiwari Vijay K VK
Nature communications 20130101
Topoisomerases resolve torsional stress, while their function in gene regulation, especially during cellular differentiation, remains unknown. Here we find that the expression of topo II isoforms, topoisomerase IIα and topoisomerase IIβ, is the characteristic of dividing and postmitotic tissues, respectively. In embryonic stem cells, topoisomerase IIα preferentially occupies active gene promoters. Topoisomerase IIα inhibition compromises genomic integrity, which results in epigenetic changes, al ...[more]
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Project description:This SuperSeries is composed of the following subset Series: GSE27245: Expression data from Top2β KO cells as well ICRF-193 treatment of in vitro derived neurons and cortical glutamatergic neurons GSE27246: Top2β ChIP-chip Refer to individual Series
2012-05-01 | E-GEOD-27247 | biostudies-arrayexpress
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. Chromatin IP was performed with Top2α antibodies in WT ES cells and hybridized to custom designed tiling array.
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Project description:Chromatin IP was performed with Top2β antibodies in WT neurons and hybridized to custom designed tiling array. HD 2.1 (custom- made)
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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.
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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.
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Project description:Cellular differentiation entails reprogramming of the transcriptome from a pluripotent to a unipotent fate. This process was suggested to coincide with a global increase of repressive heterochromatin, which results in a reduction of transcriptional plasticity and potential. Here we report the dynamics of the transcriptome and an abundant heterochromatic histone modification, dimethylation of histone H3 at lysine 9 (H3K9me2), during neuronal differentiation of embryonic stem cells. In contrast to the prevailing model, we find H3K9me2 to occupy over 50% of chromosomal regions already in stem cells. Marked are most genomic regions that are devoid of transcription and a subgroup of histone modifications. Importantly, no global increase occurs during differentiation, but discrete local changes of H3K9me2 particularly at genic regions can be detected. Mirroring the cell fate change many genes show altered expression upon differentiation. Quantitative sequencing of transcripts reveals however that the total number of active genes is equal between stem cells and several tested differentiated cell types. Together, these findings reveal high prevalence of a heterochromatic mark in stem cells and challenge the model of low abundance of epigenetic repression and resulting global transcription in stem cells. Instead cellular differentiation entails local rather than global changes in epigenetic repression and transcriptional activity. Our dataset comprises of 2 ChIP-seq samples using chromatin from embryonic stem (ES) cells and derived terminal neurons (TN) which was immunoprecipitated, using antibodies against H3K27me3 and H3K4me2. For the same cells we generated H3K9me2 ChIP-chip samples in biological replicates. For ES cells, neurons and mouse embryonic fibroblasts (MEFs) we generated biological replicates of RNA-seq data.
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