The polyploid state plays a tumor suppressive role in the liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE108645 | GEO | 2019/01/01
REPOSITORIES: GEO
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Project description:BACKGROUND & AIMS: Thirty to ninety percent of hepatocytes contain whole genome duplications, making it imperative to understand the fates and functions of these polyploid cells and how they affect development of liver disease. An important question is how polyploid cells respond to chronic proliferative demands, which are characteristic of liver diseases, but a challenging situation for cells with multiple genomes. METHODS: To interrogate liver polyploidy, we employed a mouse with reversible ANLN ( Anillin actin binding protein) knockdown that drives hepatocyte polyploidization in a doxycycline inducible fashion. Diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) were used to induce chronic liver damage and hepatocellular carcinoma (HCC). We performed partial hepatectomies to test regeneration and RNA-seq to assess gene expression changes. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. In vivo imaging of mitotic hepatocytes estimated the frequency of aneuploidy during regeneration, and exome sequencing of 54 human cirrhotic nodules was used to quantify aneuploidy. RESULTS: Hepatocytes from mice given chronic CCl4 alone showed significant increases in ploidy. Super-polyploid mice with 97% polyploid hepatocytes, due to induced knockdown of Anln , were almost completely protected from tumorigenesis induced by DEN and chronic CCl4 . The protection was not associated with differences in regenerative capacity, tissue fitness, gene regulation, or mitotic errors. Regenerative contributions from a non-hepatocyte population were ruled out using lineage tracing, confirming that polyploids can replenish tissues during chronic damage. No lagging chromosomes or micronuclei were found in mitotic polyploid cells and there was no evidence of chromosomal copy number variations in 54 nodules, suggesting that aneuploidy is not a common outcome of polyploid cell divisions. CONCLUSION: During chronic injury, polyploid hepatocytes readily divide and regenerate while being buffered from tumor suppressor loss and tumorigenesis. Therapeutic strategies to increase numbers of polypoid hepatocytes could prevent cancer while preserving regeneration.
2020-02-12 | GSE145084 | GEO
Project description:Although closely related to plant evolution, polyploid sRNAs (small RNAs) were seldom studied with experiments, especially on genome-wide range. In this study, a rice twin-seeding (two seedlings from the same grain) line SARII-658 was employed to isolate autotriploids. Those autotriploids possess unique merits to study the two interesting topics: (i) natural polyploids; (ii) the autonomy of epigenetic variations (i.e. sRNAs) from genome doubling per se. sRNA libraries were prepared from those diploid-autotriploid twin-seedlings and then were sequenced to produce 13,308,226 short sequence reads in total. Out of the 35,429 miRNA genes and siRNA clusters, 1,547 (4.36%) changed their expression levels for two folds or above after genome doubling (thereinafter, referred those sRNAs as ploidy-sensitive). The expression-unregulated sRNAs (3.71%) were far more than the downregulated ones (0.64%), suggesting that the negative regulation of the coding gene by sRNA increase is more prevalent than the positive regulation during genome doubling. The expression of sRNAs were obviously increased and biased to accumulate toward centromeric and heterochromatic regions, suggesting that sRNAs should play a role in repressing transposition activity during genome doubling. Except transposition activity, the targets of those ploidy-sensitive sRNAs involved many kinds of gene function categories, suggesting an overall regulation of sRNAs to polyploid biological processes. Findings from this study will provide theoretical bases for elucidating epigenetic mechanism of plant and sRNA evolution via genome doubling. Examination of 2 different small RNA expression profilings in 2 ploidy plants.
2009-07-15 | E-GEOD-14462 | biostudies-arrayexpress
Project description:Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a new mechanism of cell division control in the postnatal liver, in which Wnt/βcatenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. Tbx3 directly represses transcription of E2F7 and E2F8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a new paradigm for exploring how commonly active developmental signals impact cell cycle completion.
2022-07-02 | GSE205339 | GEO
Project description:The Squalius alburnoides complex (Steindachner) is one of the most intricate hybrid polyploid systems known in vertebrates. In this complex, the constant switch of the genome composition in consecutive generations, very frequently involving a change on the ploidy level, promotes repetitive situations of potential genomic shock. Previously in this complex, it was shown that in response to the increase in the genome dosage, triploid hybrids could regulate gene expression to a diploid state. In this work, we compared the small RNA profiles in the different genomic compositions interacting in the complex. Using high-throughput arrays and sequencing technologies, we were able to verify that diploid and triploid hybrids were closely related: they shared most of their sequences and their miRNA expression profiles were highly correlated. However, an overall view indicates an up-regulation of a substantial number of miRNAs in triploids. Also, the global miRNA expression in triploids was higher than predicted from an additive model. These results point to a participation of miRNAs in the cellular functional stability needed when the ploidy change. In this study, miRNA expression from 3 adult tissues (brain, muscle and liver) from 3 individuals of each genomic composition (PAA, PA, AA and PP) was analysed using microarrays.
2013-01-02 | E-GEOD-36894 | biostudies-arrayexpress
Project description:Mesenchymal stromal cells (MSCs) are used extensively in clinical trials; however, the potential for malignant transformation of MSCs has been raised. We examined the genomic stability versus the tumor forming capacity of multiple mouse MSCs. Murine MSCs have been shown to be less stable and more prone to malignant transformation than their human counterparts. A large series of independently isolated MSC populations exhibited low tumorigenic potential under syngeneic conditions, which increased in immune-compromised animals. Unexpectedly, higher ploidy correlated with reduced tumor forming capacity. Furthermore, in both cultured MSCs and primary hepatocytes, polyploidization was associated with a dramatic decrease in the expression of the long non-coding RNA H19. Direct knockdown of H19 expression in diploid cells resulted in acquisition of polyploid cell traits. Moreover, artificial tetraploidization of diploid cancer cells led to a reduction of H19 levels, as well as to an attenuation of the tumorigenic potential. Polyploidy might therefore serve as a protective mechanism aimed at reducing malignant transformation through the involvement of the H19 regulatory long non-coding RNA. Overall, six different samples are compared, three diploid biological replicate diploid MSCs, and three tetraploid biological replicate MSCs.
2012-10-21 | E-GEOD-39410 | biostudies-arrayexpress
Project description:The Squalius alburnoides complex (Steindachner) is one of the most intricate hybrid polyploid systems known in vertebrates. In this complex, the constant switch of the genome composition in consecutive generations, very frequently involving a change on the ploidy level, promotes repetitive situations of potential genomic shock. Previously in this complex, it was shown that in response to the increase in the genome dosage, triploid hybrids could regulate gene expression to a diploid state. In this work, we compared the small RNA profiles in the different genomic compositions interacting in the complex. Using high-throughput arrays and sequencing technologies, we were able to verify that diploid and triploid hybrids were closely related: they shared most of their sequences and their miRNA expression profiles were highly correlated. However, an overall view indicates an up-regulation of a substantial number of miRNAs in triploids. Also, the global miRNA expression in triploids was higher than predicted from an additive model. These results point to a participation of miRNAs in the cellular functional stability needed when the ploidy change. 4 samples were analyzed corresponding to 4 genomic constitutions: PAA, PA, AA and PP. For each sample, a library based on 3 individuals of the same genomic constitution was prepared. From each individual, 3 types of tissues were collected for RNA extraction (brain, liver and muscle).
2013-01-02 | E-GEOD-38691 | biostudies-arrayexpress
Project description:To examine gene expression changes duging aging in polyploid and diploid hepatocytes, diploid and polyploid hepatocytes were sorted from young and aged multi-reporter mice and their gene expressions were analyzed by high-throughput RNA sequence.
2021-04-14 | GSE161171 | GEO
Project description:Although closely related to plant evolution, polyploid sRNAs (small RNAs) were seldom studied with experiments, especially on genome-wide range. In this study, a rice twin-seeding (two seedlings from the same grain) line SARII-658 was employed to isolate autotriploids. Those autotriploids possess unique merits to study the two interesting topics: (i) natural polyploids; (ii) the autonomy of epigenetic variations (i.e. sRNAs) from genome doubling per se. sRNA libraries were prepared from those diploid-autotriploid twin-seedlings and then were sequenced to produce 13,308,226 short sequence reads in total. Out of the 35,429 miRNA genes and siRNA clusters, 1,547 (4.36%) changed their expression levels for two folds or above after genome doubling (thereinafter, referred those sRNAs as ploidy-sensitive). The expression-unregulated sRNAs (3.71%) were far more than the downregulated ones (0.64%), suggesting that the negative regulation of the coding gene by sRNA increase is more prevalent than the positive regulation during genome doubling. The expression of sRNAs were obviously increased and biased to accumulate toward centromeric and heterochromatic regions, suggesting that sRNAs should play a role in repressing transposition activity during genome doubling. Except transposition activity, the targets of those ploidy-sensitive sRNAs involved many kinds of gene function categories, suggesting an overall regulation of sRNAs to polyploid biological processes. Findings from this study will provide theoretical bases for elucidating epigenetic mechanism of plant and sRNA evolution via genome doubling.
2009-07-15 | GSE14462 | GEO
Project description:Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8-azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase (HPRT), suggesting an elevated gene-dosage of HPRT in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-Diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy.
2015-10-03 | GSE73710 | GEO
Project description:How allopolyploids are able not only to cope but profit from their condition is a question that remain elusive, but of great importance within the wide context of successful hybrid polyploid evolution. One outstanding example of successful allopolyploidy is the endemic Iberian S. alburnoides fish complex. Previously, based on the evaluation of 7 genes, it was reported that the transcription levels between diploid and triploid hybrid S. alburnoides were similar. If this phenomenon would occur on a full genomic scale, a wide functional diploidization could be related to the success of polyploids. We generated RNA-seq data from whole juvenile fish and from an adult tissue, to perform the first comparative quantitative transcriptomic analysis between ploidy levels of a vertebrate allopolyploid. We found 64% in juvenilesM-b full body samples and 44% in liver samples of similar expression between diploid and triploid hybrids, and those genes are mostly involved in processes of basal biological maintenance of the cells. Yet, respectively only 29% and 15% of transcripts presented accurate dosage compensation. Therefore, an exact functional diploidization of the triploid genome does not occur, but globally a significant down regulation of gene expression in triploids was observed. We find that for those genes which show similar expression levels in diploids and triploids, expression in triploids is not globally strictly proportional to gene dosage nor is it set to a perfect diploid level. This quantitative flexibility of expression may be a strong contributor to overcome the 'genomic shock', and be an immediate evolutionary advantage of allopolyploids. Genotypes: Squalius alburnoides is an allopolyploid cyprinid, resulting from interspecific hybridization between females of Squalius pyrenaicus (P genome) and males of a now extinct species related to Anaecypris hispanica (A genome). S. alburnoides natural populations arecomposed of animals of different ploidy levels and genomic constitutions (different genotypes). The predominant S. alburnoides complex intervenients in the Iberian Peninsula southern rivers are the hybrid triploid PAA, diploid PA, the parental-like diploid AA and the parental species S. pyrenaicus PP.
2015-06-24 | E-MTAB-3174 | biostudies-arrayexpress