SOX2 phosphorylation during mitosis limits genomic damage [ChIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277316 | GEO | 2025/11/14
REPOSITORIES: GEO
Similar Datasets
Project description:Pioneer transcription factors (TFs) such as SOX2 play critical roles in control of stem cell identity and are dysregulated in many human cancers. For example, SOX2 regulates the self-renewal of neural stem cells (NSCs), and is typically highly expressed in glioblastoma stem cells, where it is known to induce an immature NSC-like state. Here, we explored the regulation of SOX2 by phosphorylation during cell division and identify an unexpected role for mitotic SOX2 as an inducer of genomic damage. We find that SOX2 adopts a distinct phosphorylated state in NSCs during mitosis, regulated by the mitotic kinase CDK1. Mapping of SOX2 genome occupancy and chromatin accessibility shows that a subset of SOX2 remains bound to the interphase targets, consistent with mitotic bookmarking, but phosphorylated SOX2 is redistributed to constitutive heterochromatin, including telomeres. Ablation of SOX2 phosphorylation leads to promiscuous chromatin binding across the genome and triggers prolonged mitotic transit times and increased susceptibility to DNA damage. These findings show that excessive levels of SOX2 protein in mitosis trigger inappropriate opening of chromatin and downstream chromosomal damage. Elevated levels of SOX2 in cancers may therefore have dual oncogenic roles: imposing stemness during interphase via their well-known transcriptional roles, but simultaneously inducing genomic damage during mitosis due to their unconstrained pioneer factor activity.
2025-11-14 | GSE307412 | GEO
Project description:Pioneer transcription factors (TFs) such as SOX2 play critical roles in control of stem cell identity and are dysregulated in many human cancers. For example, SOX2 regulates the self-renewal of neural stem cells (NSCs), and is typically highly expressed in glioblastoma stem cells, where it is known to induce an immature NSC-like state. Here, we explored the regulation of SOX2 by phosphorylation during cell division and identify an unexpected role for mitotic SOX2 as an inducer of genomic damage. We find that SOX2 adopts a distinct phosphorylated state in NSCs during mitosis, regulated by the mitotic kinase CDK1. Mapping of SOX2 genome occupancy and chromatin accessibility shows that a subset of SOX2 remains bound to the interphase targets, consistent with mitotic bookmarking, but phosphorylated SOX2 is redistributed to constitutive heterochromatin, including telomeres. Ablation of SOX2 phosphorylation leads to promiscuous chromatin binding across the genome and triggers prolonged mitotic transit times and increased susceptibility to DNA damage. These findings show that excessive levels of SOX2 protein in mitosis trigger inappropriate opening of chromatin and downstream chromosomal damage. Elevated levels of SOX2 in cancers may therefore have dual oncogenic roles: imposing stemness during interphase via their well-known transcriptional roles, but simultaneously inducing genomic damage during mitosis due to their unconstrained pioneer factor activity.
2025-11-14 | GSE276865 | GEO
Project description:Pioneer transcription factors (TFs) such as SOX2 play critical roles in control of stem cell identity and are dysregulated in many human cancers. For example, SOX2 regulates the self-renewal of neural stem cells (NSCs), and is typically highly expressed in glioblastoma stem cells, where it is known to induce an immature NSC-like state. Here, we explored the regulation of SOX2 by phosphorylation during cell division and identify an unexpected role for mitotic SOX2 as an inducer of genomic damage. We find that SOX2 adopts a distinct phosphorylated state in NSCs during mitosis, regulated by the mitotic kinase CDK1. Mapping of SOX2 genome occupancy and chromatin accessibility shows that a subset of SOX2 remains bound to the interphase targets, consistent with mitotic bookmarking, but phosphorylated SOX2 is redistributed to constitutive heterochromatin, including telomeres. Ablation of SOX2 phosphorylation leads to promiscuous chromatin binding across the genome and triggers prolonged mitotic transit times and increased susceptibility to DNA damage. These findings show that excessive levels of SOX2 protein in mitosis trigger inappropriate opening of chromatin and downstream chromosomal damage. Elevated levels of SOX2 in cancers may therefore have dual oncogenic roles: imposing stemness during interphase via their well-known transcriptional roles, but simultaneously inducing genomic damage during mitosis due to their unconstrained pioneer factor activity.
2025-11-14 | GSE276848 | GEO
Project description:During mitosis, RNA polymerase and most transcription factors are excluded from the chromosomes and transcription ceases. The transcriptional re-activation of the genome, following mitosis, requires the re-setting of cell-type specific programs that were initially established during development. However, only about one-fifth of transcription factors are retained on chromosomes throughout mitosis and a subset of these have been shown to facilitate target gene reactivation during mitotic exit. How such M-bM-^@M-^\bookmarkingM-bM-^@M-^] factors bind to chromatin in mitosis and re-activate transcription is central to the stability of transcriptional programs across multiple cell cycles. We compared a diverse set of transcription factors involved in liver differentiation and found different modes of mitotic chromosome binding. The pioneer transcription factor FoxA1, which is among the first to bind liver genes in development, exhibits virtually complete mitotic chromosome binding, whereas other liver factors bind with a range of efficiencies. Yet genome-wide analysis shows that only about 15% of the FoxA1 interphase target sites are bound in mitosis; the latter include sites at genes for maintaining cell differentiation. FoxA1 mutants that perturb specific and nonspecific DNA binding reveal a significant contribution of nonspecific binding events in mitotic chromatin. Such nonspecific binding appears to spread from interphase FoxA1 targets and may serve as storage sites. The hierarchy of specific binding, nonspecific binding, partial chromatin binding, and failure to bind mitotic chromosomes reflects the temporal sequence of the factorsM-bM-^@M-^Y developmental roles in gene activation. Three replicate chIP-seq data sets each are included for mitotic and asynchronously cycling cells; a single input lane from each condition is also included.
2013-03-31 | E-GEOD-39241 | biostudies-arrayexpress
Project description:During mitosis, RNA polymerase and most transcription factors are excluded from the chromosomes and transcription ceases. The transcriptional re-activation of the genome, following mitosis, requires the re-setting of cell-type specific programs that were initially established during development. However, only about one-fifth of transcription factors are retained on chromosomes throughout mitosis and a subset of these have been shown to facilitate target gene reactivation during mitotic exit. How such “bookmarking” factors bind to chromatin in mitosis and re-activate transcription is central to the stability of transcriptional programs across multiple cell cycles. We compared a diverse set of transcription factors involved in liver differentiation and found different modes of mitotic chromosome binding. The pioneer transcription factor FoxA1, which is among the first to bind liver genes in development, exhibits virtually complete mitotic chromosome binding, whereas other liver factors bind with a range of efficiencies. Yet genome-wide analysis shows that only about 15% of the FoxA1 interphase target sites are bound in mitosis; the latter include sites at genes for maintaining cell differentiation. FoxA1 mutants that perturb specific and nonspecific DNA binding reveal a significant contribution of nonspecific binding events in mitotic chromatin. Such nonspecific binding appears to spread from interphase FoxA1 targets and may serve as storage sites. The hierarchy of specific binding, nonspecific binding, partial chromatin binding, and failure to bind mitotic chromosomes reflects the temporal sequence of the factors’ developmental roles in gene activation. Gene expression was assessed in asynchronously cycling cells in order to determine whether FoxA1 is disposed to bind to high- or low-expressed genes during mitosis. Heatmap analysis shows that FoxA1's mitotic targets are among the highest-expressed genes in asynchronous cells. Total RNA was collected from three different plates with asynchronous HUH7 cells using the RNeasy mini kit (Qiagen Valencia CA). Expression microarrays were performed with a Human Gene 1.OST array (Affymetrix) at the UPenn Microarray Core Facility and assessed using Partek.
2013-03-31 | E-GEOD-39208 | biostudies-arrayexpress
Project description:Eukaryotic translation initiation factor 4E (eIF4E)–binding protein 1 (4E-BP1) inhibits cap-dependent translation in eukaryotes by competing with eIF4G for an interaction with eIF4E. Phos-phorylation at Ser-83 of 4E-BP1 occurs during mitosis through the activity of cyclin-dependent kinase 1 (CDK1)/cyclin B rather than through canonical mTOR kinase activity. Here, we investi-gated the interaction of eIF4E with 4E-BP1 or eIF4G during interphase and mitosis. We observed that 4E-BP1 and eIF4G bind eIF4E at similar levels during interphase and mitosis. The most highly phosphorylated mitotic 4E-BP1 isoform (δ) did not interact with eIF4E, whereas a distinct 4E-BP1 phospho-isoform, EB-γ—phosphorylated at Thr-70, Ser-83, and Ser-101—bound to eIF4E during mitosis. Two-dimensional gel electropho-retic analysis corroborated the identity of the phosphorylation marks on the eIF4E-bound 4E-BP1 isoforms and uncovered a population of phosphorylated 4E-BP1 molecules lacking Thr-37/Thr-46–priming phosphorylation. Moreover, proximity ligation assays for phospho–4E-BP1 and eIF4E revealed different in situ interactions during interphase and mitosis. The eIF4E:eIF4G interaction was not inhibited, but rather increased in mitotic cells, consistent with active translation initiation during mitosis. Phospho-defective substitution of 4E-BP1 at Ser-83 did not change global translation or individual mRNA translation profiles as measured by single-cell nascent protein synthesis and eIF4G RNA-immunoprecipitation sequencing. Mitotic 5’-terminal oligopyrimidine RNA translation was active and, unlike interphase translation, resistant to mTOR inhibition. Our findings reveal the phosphorylation profiles of 4E-BP1 isoforms and their interactions with eIF4E throughout the cell cycle and indicate that 4E-BP1 does not specifically inhibit translation initiation during mitosis.
2019-06-14 | GSE131668 | GEO
Project description:Here we compare the distribution of insulator proteins during interphase and mitosis. We performed ChIP-seq analysis on purified populations of interphase and mitotic Kc cells, using antibodies against CP190, dCTCF, BEAF, and Su(Hw). Examination of 4 different insulator proteins during interphase and mitosis
2013-01-21 | E-GEOD-32584 | biostudies-arrayexpress
Project description:During mitosis, RNA polymerase and most transcription factors are excluded from the chromosomes and transcription ceases. The transcriptional re-activation of the genome, following mitosis, requires the re-setting of cell-type specific programs that were initially established during development. However, only about one-fifth of transcription factors are retained on chromosomes throughout mitosis and a subset of these have been shown to facilitate target gene reactivation during mitotic exit. How such “bookmarking” factors bind to chromatin in mitosis and re-activate transcription is central to the stability of transcriptional programs across multiple cell cycles. We compared a diverse set of transcription factors involved in liver differentiation and found different modes of mitotic chromosome binding. The pioneer transcription factor FoxA1, which is among the first to bind liver genes in development, exhibits virtually complete mitotic chromosome binding, whereas other liver factors bind with a range of efficiencies. Yet genome-wide analysis shows that only about 15% of the FoxA1 interphase target sites are bound in mitosis; the latter include sites at genes for maintaining cell differentiation. FoxA1 mutants that perturb specific and nonspecific DNA binding reveal a significant contribution of nonspecific binding events in mitotic chromatin. Such nonspecific binding appears to spread from interphase FoxA1 targets and may serve as storage sites. The hierarchy of specific binding, nonspecific binding, partial chromatin binding, and failure to bind mitotic chromosomes reflects the temporal sequence of the factors’ developmental roles in gene activation.
2013-03-31 | GSE39241 | GEO
Project description:During mitosis, RNA polymerase and most transcription factors are excluded from the chromosomes and transcription ceases. The transcriptional re-activation of the genome, following mitosis, requires the re-setting of cell-type specific programs that were initially established during development. However, only about one-fifth of transcription factors are retained on chromosomes throughout mitosis and a subset of these have been shown to facilitate target gene reactivation during mitotic exit. How such “bookmarking” factors bind to chromatin in mitosis and re-activate transcription is central to the stability of transcriptional programs across multiple cell cycles. We compared a diverse set of transcription factors involved in liver differentiation and found different modes of mitotic chromosome binding. The pioneer transcription factor FoxA1, which is among the first to bind liver genes in development, exhibits virtually complete mitotic chromosome binding, whereas other liver factors bind with a range of efficiencies. Yet genome-wide analysis shows that only about 15% of the FoxA1 interphase target sites are bound in mitosis; the latter include sites at genes for maintaining cell differentiation. FoxA1 mutants that perturb specific and nonspecific DNA binding reveal a significant contribution of nonspecific binding events in mitotic chromatin. Such nonspecific binding appears to spread from interphase FoxA1 targets and may serve as storage sites. The hierarchy of specific binding, nonspecific binding, partial chromatin binding, and failure to bind mitotic chromosomes reflects the temporal sequence of the factors’ developmental roles in gene activation. Gene expression was assessed in asynchronously cycling cells in order to determine whether FoxA1 is disposed to bind to high- or low-expressed genes during mitosis. Heatmap analysis shows that FoxA1's mitotic targets are among the highest-expressed genes in asynchronous cells.
2013-03-31 | GSE39208 | GEO
Project description:Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that they could provide transcriptional memory through mitosis. To obtain the first genome-wide view of the dynamics of chromatin structure during mitosis, we compared the DNase sensitivity of interphase and mitotic chromatin at two stages of cellular maturation in a rapidly dividingmurine erythroblastmodel. Despite global chromosome condensation visible during mitosis at the microscopic level, the chromatin accessibility landscape is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility, whereas distal regulatory elements preferentially lose accessibility. Promoters with the highest degree of accessibility preservation in mitosis tend to also be accessible across many murine tissues in interphase. Transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but does not visibly influence mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis and are modulated at the level of individual genes and regulatory elements. Dnase-Seq data is integrated with Chip-seq [GSE36589, GSE30142] and RNA-seq to examine epigentic changes in mitosis. We performed DNase-seq on two cell lines, G1E and G1E-ER4, both on an asynchronus population, and on a sample of cells in mitosis; each of the 4 experiments in triplicate.
2014-10-01 | E-GEOD-61885 | biostudies-arrayexpress