Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123513 | GEO | 2019/04/17
REPOSITORIES: GEO
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Project description:Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy
| PRJNA509072 | ENA
Project description:The transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to establish organoids in vitro, but blocked the ability to recover from treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or both Oct1 alleles progressively increased tumor burden in a colon cancer model driven by loss-of-heterozygosity of the tumor suppressor gene Apc. The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with differentially expressed genes between the two models. Oct1 ChIPseq using HCT116 colon carcinoma cells identifies target genes associated with mitotic stability, metabolism, stress response and malignancy. This set of gene targets overlaps significantly with genes differentially expressed in the two tumor models. These results reveal that Oct1 is selectively required for recovery after colon damage, and that Oct1 has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology.
| S-EPMC6522070 | biostudies-literature
Project description:Embryonic stem cells (ESCs) co-express Oct4/POU5F1 and an Oct4 paralog known Oct1/POU2F1. To study the role of Oct1 in embryonic stem cell transcriptional control and pluripotency, we constructed germline and inducible-conditional Oct1 deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal, growth rates and metabolic signatures. However loss of Oct1 results in defective lineage specification. ESCs lacking Oct1 fail to form beating cardiomyocytes in culture, generate neurons poorly, form smaller, less differentiated teratomas, and are incapable of generating chimeric mice. Upon RA-mediated neuronal differentiation, Oct1 deficient cells fail to properly induce developmentally poised genes. Simultaneously, genes for alternative developmental pathways, most notably for the development of extra-embryonic tissues, are inappropriately expressed. ChIP experiments show that Oct1 does not occupy pluripotency genes or differentially expressed developmental targets in ESCs. Additionally, Oct1 occupies developmental targets as cells differentiate and Oct4 is lost. These results are consistent with a role for Oct1 in promoting the expression of lineage-specific genes in differentiating cells while simultaneously repressing genes specific for alternative lineages.
2017-05-24 | GSE85062 | GEO
Project description:Embryonic stem cells (ESCs) co-express Oct4/POU5F1 and an Oct4 paralog known Oct1/POU2F1. To study the role of Oct1 in embryonic stem cell transcriptional control and pluripotency, we constructed germline and inducible-conditional Oct1 deficient ESC lines. ESCs lacking Oct1 show normal appearance, self-renewal, growth rates and metabolic signatures. However loss of Oct1 results in defective lineage specification. ESCs lacking Oct1 fail to form beating cardiomyocytes in culture, generate neurons poorly, form smaller, less differentiated teratomas, and are incapable of generating chimeric mice. Upon RA-mediated neuronal differentiation, Oct1 deficient cells fail to properly induce developmentally poised genes. Simultaneously, genes for alternative developmental pathways, most notably for the development of extra-embryonic tissues, are inappropriately expressed. ChIP experiments show that Oct1 does not occupy pluripotency genes or differentially expressed developmental targets in ESCs. Additionally, Oct1 occupies developmental targets as cells differentiate and Oct4 is lost. These results are consistent with a role for Oct1 in promoting the expression of lineage-specific genes in differentiating cells while simultaneously repressing genes specific for alternative lineages.
2017-05-24 | GSE85061 | GEO
Project description:The pathways used by cells to transition from undifferentiated, pluripotent gene expression programs into cell type-specific gene expression programs are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 recruits histone lysine demethylase complexes to allow for correct induction of silent, developmental lineage-specific genes and “canalize” developmental progression. Using mesodermal differentiation of inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that the potential to progress efficiently through mesodermal development is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late presomitic mesoderm and early somite stage populations, and show “leaky” developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Cells lacking Oct1 fail to positively resolve gene bivalency and activate gene expression by removing inhibitory H3K27me3 chromatin marks at mesoderm-specific genes. The Oct1 protein interacts with and recruits UTX to lineage-specific bivalent/poised targets, explaining the failure of Oct1 deficient cells to remove H3K27me3. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.
2022-11-26 | GSE179780 | GEO
Project description:The pathways used by cells to transition from undifferentiated, pluripotent gene expression programs into cell type-specific gene expression programs are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 recruits histone lysine demethylase complexes to allow for correct induction of silent, developmental lineage-specific genes and “canalize” developmental progression. Using mesodermal differentiation of inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that the potential to progress efficiently through mesodermal development is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late presomitic mesoderm and early somite stage populations, and show “leaky” developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Cells lacking Oct1 fail to positively resolve gene bivalency and activate gene expression by removing inhibitory H3K27me3 chromatin marks at mesoderm-specific genes. The Oct1 protein interacts with and recruits UTX to lineage-specific bivalent/poised targets, explaining the failure of Oct1 deficient cells to remove H3K27me3. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.
2022-11-26 | GSE179779 | GEO
Project description:The pathways used by cells to transition from undifferentiated, pluripotent gene expression programs into cell type-specific gene expression programs are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 recruits histone lysine demethylase complexes to allow for correct induction of silent, developmental lineage-specific genes and “canalize” developmental progression. Using mesodermal differentiation of inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that the potential to progress efficiently through mesodermal development is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late presomitic mesoderm and early somite stage populations, and show “leaky” developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Cells lacking Oct1 fail to positively resolve gene bivalency and activate gene expression by removing inhibitory H3K27me3 chromatin marks at mesoderm-specific genes. The Oct1 protein interacts with and recruits UTX to lineage-specific bivalent/poised targets, explaining the failure of Oct1 deficient cells to remove H3K27me3. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.
2022-11-26 | GSE160941 | GEO
Project description:The pathways used by cells to transition between pluripotent and tissue-specific states are incompletely understood. Here we show that the widely-expressed transcription factor Oct1/Pou2f1 activates silent, developmental lineage-appropriate genes to “canalize” developmental progression. Using Oct1 inducible knockout embryonic stem cells, we show that that Oct1 deficiency impairs mesodermal and terminal muscle differentiation in a manner that can be rescued by Oct1 retroviral expression. We show that mesoderm-specific genes are not correctly induced early in the differentiation timecourse. Oct1-deficient cells lose temporal coherence in the induction of lineage-specific genes and show inappropriate developmental lineage branching, resulting in poorly differentiated cells states retaining epithelial characteristics. In embryonic stem cells, Oct1 co-binds with Oct4 to genes critical for mesoderm induction, and continues to bind these genes during differentiation. Oct1 binding events are enriched at the termini of chromatin loops, including loops gained with differentiation. The Utx/Kdm6a histone lysine demethylase also binds to many of these genes, and using a prototypic Pax3 gene we show that Oct1 recruits Utx to remove inhibitory H3K27me3 marks and activate expression. The specificity of the ubiquitous Oct1 protein for mesodermal genes can be explained by cooperative interactions with lineage-driving Smad transcription factors, as we show that Smad and Oct binding sites frequently coexist mesoderm-specific genes, and that Oct1 and Smad3 act cooperatively at the Myog enhancer. Overall, these results identify Oct1 as a key mediator of the induction of mesoderm lineage-specific genes.
2022-11-26 | GSE207828 | GEO
Project description:The pathways used by cells to transition from undifferentiated, pluripotent gene expression programs into cell type-specific gene expression programs are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 recruits histone lysine demethylase complexes to allow for correct induction of silent, developmental lineage-specific genes and “canalize” developmental progression. Using mesodermal differentiation of inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that the potential to progress efficiently through mesodermal development is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late presomitic mesoderm and early somite stage populations, and show “leaky” developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Cells lacking Oct1 fail to positively resolve gene bivalency and activate gene expression by removing inhibitory H3K27me3 chromatin marks at mesoderm-specific genes. The Oct1 protein interacts with and recruits UTX to lineage-specific bivalent/poised targets, explaining the failure of Oct1 deficient cells to remove H3K27me3. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.
2022-11-26 | GSE160940 | GEO
Project description:The pathways used by cells to transition from undifferentiated, pluripotent gene expression programs into cell type-specific gene expression programs are incompletely understood. Here we show that the transcription factor Oct1/Pou2f1 recruits histone lysine demethylase complexes to allow for correct induction of silent, developmental lineage-specific genes and “canalize” developmental progression. Using mesodermal differentiation of inducible-conditional Oct1 knockout embryonic stem cells and single-cell gene expression profiling, we show that the potential to progress efficiently through mesodermal development is impaired in the Oct1 deficient condition. Oct1 deficient cells fail to form late presomitic mesoderm and early somite stage populations, and show “leaky” developmental trajectories with inappropriate lineage branching and accumulation of poorly differentiated cells that retain gene expression and metabolic hallmarks of pluripotency. Oct1 directly binds and regulates genes critical for developmental regulation, including genes encoding mesoderm-specific master regulators and components of chromatin regulatory complexes. Cells lacking Oct1 fail to positively resolve gene bivalency and activate gene expression by removing inhibitory H3K27me3 chromatin marks at mesoderm-specific genes. The Oct1 protein interacts with and recruits UTX to lineage-specific bivalent/poised targets, explaining the failure of Oct1 deficient cells to remove H3K27me3. Ectopic Oct1 expression improves the ability of cells to differentiate accurately under mesoderm lineage-inducing conditions.
2022-11-26 | GSE160942 | GEO