Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumor-propagating cells and their dynamic cellular transition during liver cancer progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA752329 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15353200_1.fastq.gz | Fastqsanger.gz | |||
| SRR15353200_2.fastq.gz | Fastqsanger.gz | |||
| SRR15353201_1.fastq.gz | Fastqsanger.gz | |||
| SRR15353201_2.fastq.gz | Fastqsanger.gz | |||
| SRR15353202_1.fastq.gz | Fastqsanger.gz |
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2021-10-04 | GSE181515 | GEO
Project description:Purpose: The function of Prom1, a penta-transmembrane glycoprotein which is a used as cancer stem cell marker, in the liver is unclear. The goal of this study is to examine the effect of Prom1 -/- in mouse primary hepatocyte transcriptomes. Prominin-1 (Prom1) is a major cell surface marker of cancer stem cells, but its physiological functions in the liver have not been elucidated. We analyzed the levels of mRNA transcripts in serum-starved primary Prom1+/+ and Prom1-/- mouse hepatocytes using RNA-sequencing (RNA-seq) data, and found that CREB target genes were down-regulated. This initial observation led us to determine that the Prom1 deficiency inhibited cAMP response element binding protein (CREB) activation and gluconeogenesis, but not cyclic AMP (cAMP) accumulation, in glucagon-, epinephrine-, or forskolin-treated liver tissues and primary hepatocytes, and mitigated glucagon-induced hyperglycemia. Because Prom1 interacted with radixin, the Prom1 deficiency prevented radixin from localizing to the plasma membrane. Moreover, systemic adenoviral knockdown of radixin inhibited CREB activation and gluconeogenesis in glucagon-treated liver tissues and primary hepatocytes, and mitigated glucagon-elicited hyperglycemia. Based on these results, we conclude that Prom1 regulates hepatic PKA signaling via radixin functioning as an A kinase-anchored protein (AKAP).
2020-01-22 | GSE144018 | GEO
Project description:Prom1, also knwon as CD133 is a stem cell marker that are down-regulated during developmental process. Here we first reports that PROM1 is a regulator of expression of specific sets of genes from DRG neurons.
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Project description:Multi-colour lineage tracing reveals intra-stage proliferative heterogeneity during mammary tumour progression
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Project description:BACKGROUND: Phase transition widely exists in the biological world, such as transformation of cell cycle phases, cell differentiation stages, disease development, and so on. Such a nonlinear phenomenon is considered as the conversion of a biological system from one phenotype/state to another. Studies on the molecular mechanisms of biological phase transition have attracted much attention, in particular, on different genotypes (or expression variations) in a specific phase, but with less of focus on cascade changes of genes' functions (or system state) during the phase shift or transition process. However, it is a fundamental but important mission to trace the temporal characteristics of a biological system during a specific phase transition process, which can offer clues for understanding dynamic behaviors of living organisms. RESULTS: By overcoming the hurdles of traditional time segmentation and temporal biclustering methods, a causal process model (CPM) in the present work is proposed to study the biological phase transition in a systematic manner, i.e. first, we make gene-specific segmentation on time-course expression data by developing a new boundary gene estimation scheme, and then infer functional cascade dynamics by constructing a temporal block network. After the computational validation on synthetic data, CPM was used to analyze the well-known Yeast cell cycle data. It was found that the dynamics of the boundary genes are periodic and consistent with the phases of the cell cycle, and the temporal block network indeed demonstrates a meaningful cascade structure of the enriched biological functions. In addition, we further studied protein modules based on the temporal block network, which reflect temporal features in different cycles. CONCLUSIONS: All of these results demonstrate that CPM is effective and efficient comparing to traditional methods, and is able to elucidate essential regulatory mechanism of a biological system even with complicated nonlinear phase transitions.
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Project description:MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine 79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1 which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
2020-03-25 | GSE135024 | GEO
Project description:MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine 79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1 which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
2020-03-25 | GSE135023 | GEO
Project description:MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine 79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1 which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
2020-03-25 | GSE135025 | GEO
Project description:Alternative splicing (AS) is a crucial mechanism contributing to proteomic diversity, which is highly regulated in tissue-specific and development-specific patterns. Retinal tissue exhibits one of the highest levels of AS. In particular, photoreceptors have a distinctive AS pattern involving the inclusion of microexons not found in other cell types. PROM1 whose encoded protein Prominin-1 is located in photoreceptor outer segments (OSs), undergoes exon 4 inclusion from the 12th post-conception week of human development through adulthood. Exon 4 skipping in PROM1 is associated with late-onset mild maculopathy, however its role in photoreceptor maturation and function is unknown. In this study retinal organoids, a valuable model system, were employed in combination with phosphorodiamidate morpholino oligos (PMOs) to assess the role of exon 4 AS in the development of human retina. Our data demonstrate that 55% skipping of PROM1 exon 4 resulted in decreased Prominin-1 expression by 40%, detectable photoreceptor cilium defects and impaired transport of specific OS proteins in cone photoreceptors, such as cone opsin. Transcriptomic and Western blot analyses revealed decreased expression of cone, inner segment and connecting cilium basal body markers, and increased expression of genes associated with stress response and the ubiquitin-proteasome system, and downregulation of autophagy. Together these data indicate that cones may be more sensitive to PROM1 exon 4 skipping, corroborating the pathogenesis of late-onset mild maculopathy. Importantly, the use of retinal organoids provides a valuable platform to study AS and unravel disease mechanisms in a more physiologically relevant context, opening avenues for further research and potential therapeutic interventions.
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Project description:Stem cells have long been regarded as a potential origin of cancer. But cancers could also arise from mutated, differentiated cells that reacquire stem cell properties. Here, in mice harboring conditional oncogenic and lineage tracing alleles, we show that cancers develop from Prom1+ (CD133) cells, only in organs where these cells operate as stem cells. Allograft assays demonstrated that these cancers are not necessarily propagated by Prom1+ cancer stem cells, even when initiated in Prom1-lineages that maintain the normal organ. Normal and transformed Prom1+ stem cells in our mice, maintained the gastric mucosa and gastric adenocarcinomas, respectively. Comparison of these cells identified the latent sodium channel gene Nalcn as a novel gastric cancer suppressor that regulates the differentiation of stomach stem cell daughters. Our data provide new evidence that cancers are initiated preferentially within stem cells, and important insights into how these cells are deregulated to initiate and maintain cancers Prom1 conditional mutants in mice that develped tumors and normal from cells various tissues in mice are compared. 117 samples were studied.
2013-09-01 | E-GEOD-40634 | biostudies-arrayexpress