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Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7 deficient livers.

ABSTRACT: PR-SET7-mediated histone-4 lysine-20 methylation has been implicated in mitotic condensation, DNA damage response and replication licencing. Here we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis. Necrotic death was accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic-regenerative cycles coupled with oncogenic STAT3 activation replaced pre-existing hepatocytes with hepatocellular carcinoma derived entirely from cells with cancer stem cell characteristics. Hepatocellular carcinoma in these mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE61567 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA261487

REPOSITORIES: GEO

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PR-SET7 inactivation causes hepatocyte necrosis and spontaneous development of hepatocellular carcinoma derived from ductal progenitor cells

Project description:PR-SET7-mediated histone-4 lysine-20 methylation has been implicated in mitotic condensation, DNA damage response and replication licencing. Here we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis with unusual features of autophagy, termed "endonucleosis". Necrotic death was accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic-regenerative cycles coupled with oncogenic STAT3 activation replaced pre-existing hepatocytes with hepatocellular carcinoma derived entirely from ductal progenitor cells. Hepatocellular carcinoma in these mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. Mice carrying hepatocyte specific inactivation of PR-SET7 were generated in order to investigate the function of PR-SET7 histone methyl transferase in liver organogenesis, hepatocyte proliferation and liver regeneration. P15 WT mice were injected intra-peritoneally (ip) with 25ml per kg DEN (diethyl nitrosamine). Mice were examined for RNA expression at 8 months old.

2014-08-01 | E-GEOD-49555 | biostudies-arrayexpress

PR-SET7 inactivation causes hepatocyte necrosis and spontaneous development of hepatocellular carcinoma derived from ductal progenitor cells

2014-08-01 | GSE49555 | GEO

Gene expression in the mTSCs of WT and Pr-set7 KO mTSCs

Project description:To detect the gene profiles in WT and Pr-set7 KO mTSCs, mTSCs are collected and subjected to RNA-Seq. After aligned to mouse mm10 by HISAT2, RPKM value was calculated by Edger. Our results show that Pr-set7 as the key regulator for mTSCs. There are also some genes differentially expressed after Pr-set7 KO, some of the DEGs were further confirmed by qPCR, the DEGs were associated with viral mimic inflammatory activities, antiviral innate immune response, genomic instability, and programmed cell death, indicating the essential role of Pr-set7. This RNA-Seq data provides fundamental information for our further physiological study of Pr-set7.

2023-06-28 | GSE196224 | GEO

Gene expression in the hTSCs of si-NC and si-PR-SET7 KD hTSCs

Project description:To detect the gene profiles in si-NC and si-PR-SET7 KD hTSCs, hTSCs are collected and subjected to RNA-Seq. After aligned to mouse hg38 by HISAT2, RPKM value was calculated by Edger. Our results show that PR-SET7 as the key regulator for hTSCs. There are also some genes differentially expressed after PR-SET7 KD, some of the DEGs were further confirmed by qPCR, the DEGs were associated with viral mimic inflammatory activities, antiviral innate immune response, genomic instability, and programmed cell death, indicating the essential role of PR-SET7. This RNA-Seq data provides fundamental information for our further physiological study of PR-SET7.

2023-06-28 | GSE196223 | GEO

Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation

Project description:The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggest that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr-set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr-Set7 is a novel regulator of NSC reactivation. Loss-of-function of pr-set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC-specific in vivo profiling, we demonstrate that Pr-set7 binds to the promoter region of cyclin dependent kinase 1 (cdk1) and Wnt pathway transcriptional co-activator earthbound1/jerky (ebd1). Further validation indicates that Pr-set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr-set7, Cdk1 and Ebd1 promote NSC reactivation. Moreover, Cdk1 upregulates the Ebd1 levels in NSCs, while Ebd1 appears to downregulate Cdk1 expression, suggesting a negative feedback regulation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7, the sole H4K20 methyltransferase, promotes NSC reactivation through regulating Wnt signaling and cell-cycle progression. Given the conservation of Pr-set7, our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 in NSC proliferation and associated neurodevelopmental disorders.

2021-02-09 | GSE158764 | GEO

Mus musculus

Project description:PR-SET7 inactivation causes hepatocyte necrosis and spontaneous development of hepatocellular carcinoma derived from ductal progenitor cells

| PRJNA214241 | ENA

The UBC9 E2 SUMO conjugating enzyme binds the PR-Set7 histone methyltransferase to facilitate target gene repression

Project description:To detect genes whose expression is signigicantly altered upon depletion of pr-SET7 Total RNA obtained from 4 days post-transfection of control pSuperior empty plasmid and pSuperior pr-SET7 shRNA plasmid

2011-07-02 | E-GEOD-30361 | biostudies-arrayexpress

Methylation of histone H4 lysine 20 by PR-Set7 ensures the integrity of late replicating sequence domains in Drosophila

Project description:The methylation state of lysine 20 on histone H4 (H4K20) has been linked to cell cycle progression, Origin Recognition Complex (ORC) binding, and replication origin regulation. Monomethylation of H4K20 (H4K20me1) is mediated by the cell cycle-regulated histone methyltransferase PR-Set7, which is essential for genome integrity and cell cycle progression. PR-Set7 depletion in mammalian cells results in defective S-phase progression and the accumulation of DNA damage, which could be partially attributed to a defect in pre-Replication Complex (pre-RC) formation and origin activity. However, these studies were limited to a handful of mammalian origins, and it remains unclear how PR-Set7 and H4K20 methylation impact the replication program on a genomic scale. Using Drosophila Kc167 cells, we employed genetic, cytological, and genomic approaches to better understand the role of PR-Set7 and H4K20 methylation in regulating DNA replication and governing genome stability. We find that depletion of Drosophila PR-Set7 and loss of H4K20me1 result in the accumulation of DNA damage and an ATR-dependent cell cycle arrest. The cell cycle arrest occurs during the second S-phase following loss of PR-Set7 activity, suggesting that accumulation of nascent H4K20 is recalcitrant to the DNA replication program. Deregulation of H4K20 methylation had no impact on origin activation throughout the genome; instead, we found that the DNA damage marker, phosphorylated H2A.v (γ-H2A.v), accumulated specifically in late replicating domains in the absence of PR-Set7. This suggests that the molecular basis for the cell cycle arrest and accumulation of DNA damage resulting from loss of PR-Set7 is stochastic fork collapse within late replicating domains.

2015-10-08 | GSE73668 | GEO

The UBC9 E2 SUMO conjugating enzyme binds the PR-Set7 histone methyltransferase to facilitate target gene repression

Project description:To detect genes whose expression is signigicantly altered upon depletion of pr-SET7

2011-07-02 | GSE30361 | GEO

Role of PARP-1 and PR-Set7 in transcriptional regulation during development (RNA-seq)

Project description:We interrogated the role of PARP-1 and PR-Set7 in developmental gene regulation in Drosophila via RNA-seq in third-instar larvae.

2023-05-25 | GSE217728 | GEO

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