Regulation of cellular heterogeneity and rates of symmetric and asymmetric divisions in triple-negative breast cancer
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ABSTRACT:
PROVIDER: PRJNA328149 | ENA |
REPOSITORIES: ENA
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Project description:Differentiation events contribute to cellular heterogeneity within tumors and influence disease progression and response to therapy. Here we dissect the mechanisms controlling intratumoral heterogeneity within basal-like breast cancers. We show that cancer cells can transition between a differentiation state related to that of normal luminal progenitors and a state closer to that of mature luminal cells, and that this occurs through asymmetric cell divisions. The Polycomb factor EZH2 and the Notch pathway act to increase the rates of symmetric divisions that produce progenitor-like cells, while the FOXA1 transcription factor promotes asymmetric divisions that reduce the numbers of such cells. Through functional screening, we identified a group of regulators that control cancer cell differentiation state and the relative proportions of tumor cell subpopulations. Our findings highlight the regulation of asymmetric cell divisions as a mechanism controlling intratumoral heterogeneity, and identify molecular pathways that control breast cancer cellular composition.
2018-08-26 | GSE84143 | GEO
Project description:Differentiation events contribute to cellular heterogeneity within tumors and influence disease progression and response to therapy. Here we dissect the mechanisms controlling intratumoral heterogeneity within basal-like breast cancers. We show that cancer cells can transition between a differentiation state related to that of normal luminal progenitors and a state closer to that of mature luminal cells, and that this occurs through asymmetric cell divisions. The Polycomb factor EZH2 and the Notch pathway act to increase the rates of symmetric divisions that produce progenitor-like cells, while the FOXA1 transcription factor promotes asymmetric divisions that reduce the numbers of such cells. Through functional screening, we identified a group of regulators that control cancer cell differentiation state and the relative proportions of tumor cell subpopulations. Our findings highlight the regulation of asymmetric cell divisions as a mechanism controlling intratumoral heterogeneity, and identify molecular pathways that control breast cancer cellular composition.
2018-08-26 | GSE84080 | GEO
Project description:Asymmetric cell divisions (ACDs) generate two daughter cells with identical genetic information but distinct cell fates. Epigenetic mechanisms are crucial for cell fate specification, and it remains unclear how epigenetic information is inherited. Here, we report asymmetric segregation of the nucleosome remodeling and deacetylase complex (NuRD) during ACDs in Caenorhabditis elegans. NuRD is enriched to chromosomes of the future surviving but not apoptotic daughter cell, whereas NuRD evenly distributes to two viable siblings. Disruption of ACDs causes symmetric NuRD inheritance, and an ectopic gain of NuRD in apoptotic daughters allows cell survival and differentiation. Lack of NuRD upregulates the expression of the vital cell death-inducing gene egl-1 by increasing H3K27 acetylation on the egl-1 locus, which activates the EGL-1-CED-9-CED-4-CED-3 pathway to promote apoptosis. We propose that biased NuRD segregation during ACDs provides a previously unrecognized yet common mechanism for asymmetrically partitioning epigenetic information that contributes to binary cell fate decisions.
2022-12-30 | GSE167379 | GEO
Project description:Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair crucial to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler INO80 in chromatin-mediated transcriptome and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break repair, triggering p53 activation, robust apoptosis, and microcephaly, whereas co-deletion of Trp53 with Ino80 leads to remarkable reversal of these phenotypes. Using an in vivo DNA repair assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from INO80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of INO80-mediated HR is dependent on the mode of NPC division: Ino80 deletion causes extensive DNA damage and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. Thus, distinct modes of NPC division have divergent requirements for Ino80-dependent HR DNA repair.
2020-06-25 | GSE133799 | GEO
Project description:Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair crucial to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler INO80 in chromatin-mediated transcriptome and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break repair, triggering p53 activation, robust apoptosis, and microcephaly, whereas co-deletion of Trp53 with Ino80 leads to remarkable reversal of these phenotypes. Using an in vivo DNA repair assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from INO80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of INO80-mediated HR is dependent on the mode of NPC division: Ino80 deletion causes extensive DNA damage and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. Thus, distinct modes of NPC division have divergent requirements for Ino80-dependent HR DNA repair.
2020-06-23 | GSE153061 | GEO
Project description:Stem cells balance cellular fates through asymmetric and symmetric divisions in order to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly defined. N6-methyladenosine (m6A), the most abundant posttranscriptional mRNA modification controls cellular states and its abundance is dysregulated in cancer. Here we show that mRNA methylation controls symmetric commitment and cell identity of hematopoietic stem cells (HSCs). Using single-cell RNA sequencing (scRNA-seq) in combination with transcriptomic profiling of HSPCs (hematopoietic stem and progenitor cells) from control and m6A methyltransferase Mettl3 conditional knockout mice, we found that m6A-deficient HSC fail to symmetrically differentiate. Dividing HSCs are expanded and are blocked in an intermediate state that molecularly and functionally resembles multipotent progenitors. Mechanistically, RNA methylation controls Myc mRNA abundance in differentiating HSCs. Importantly, we identified MYC as a new marker for HSC asymmetric and symmetric commitment. Furthermore, forced expression of MYC rescued m6A’s requirement for engraftment indicating its importance in the early stage of HSC cellular fate. Overall our results indicate that RNA methylation is critical for normal blood homeostasis and may provide a general mechanism for how stem cells regulate differentiation fate choice.
2019-07-25 | GSE132357 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-08-25 | GSE84149 | GEO
Project description:Mammary gland aging is due to aberrant activation of p66Shc, which induces p53/p44 signaling, leading to failure of symmetric divisions, decreased proliferation and reduced regenerative potential of MaSCs. Age-related changes in mammary epithelial cells derived from C57BL/6J WT and p66Shc knockedout mice cultured as stem cell-enriched mammospheres.
2022-12-21 | GSE201253 | GEO
Project description:Aging organs functionally and structurally decline with the loss of their regenerative capabilities, yet the existence of distinct cell division programs that determine organ fates is unknown. Hair follicles, mammalian mini-organs that grow hair, miniaturize by aging. Here we report that hair follicle regeneration and aging are driven by distinct cell division types of hair follicle stem cells (HFSCs). Cell fate tracing and cell division axis analysis in mice revealed that HFSCs undergo symmetric and asymmetric cell divisions to generate a new bulge, yet preferentially provoke “stress-responsive type” asymmetric cell divisions that generate aberrantly differentiating cells upon age/stress. That dynamic program with repetitive divisions efficiently eradicates those cells through defective association and stabilization of a hemidesmosomal protein COL17A1 and a cell-polarity-protein aPKCλ in HFSCs, thereby causing organ aging. The forced stabilization of COL17A1 rescued organ aging through aPKCλ stabilization. These results demonstrate that distinct cell division programs govern tissue/organ fates.
2020-12-25 | GSE124119 | GEO