Effect of SETD8/PR-Set7 knockdown on gene expression profiles in human fibroblasts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86545 | GEO | 2017/03/30
SECONDARY ACCESSION(S): PRJNA342169
REPOSITORIES: GEO
Similar Datasets
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
Project description:Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation
| PRJNA666438 | ENA
Project description:The chromatin modifying enzymes that drive the erythroid-specific transcription program are incompletely understood. Setd8 is the sole histone methyltransferase in mammals capable of generating mono-methylated histone H4 lysine 20 (H4K20me1) and is expressed at significantly higher levels in erythroid cells than any other cell- or tissue- type, suggesting that Setd8 has an erythroid-specific function. To test this hypothesis, stable knockdown of Setd8 was established in extensively self-renewing erythroblasts (ESREs), a well-characterized, non-transformed, model of erythroid maturation. Setd8 knockdown impaired erythroid maturation, characterized by a delay in hemoglobin accumulation, larger cell area, persistent kit expression, incomplete nuclear condensation, and lower rates of enucleation than control cells. Setd8 knockdown did not alter ESRE proliferation or viability, or result in accumulation of DNA damage. Global gene expression analyses following Setd8 knockdown suggests that in erythroid cells, Setd8 functions primarily as a repressor and demonstrated high levels of Gata2 expression. Setd8 occupies critical regulatory elements in the Gata2 locus, and knockdown of Setd8 resulted in loss of H4K20me1 and gain of H4 acetylation at the Gata2 1S promoter. Taken together, these results imply that Setd8 is an important regulator of erythroid maturation that works in part through repression of Gata2. RNA-seq was performed of Setd8 knockdown and control cells, both while the cells were proliferating, and after 6 hours of maturation.
2015-04-24 | E-GEOD-62647 | biostudies-arrayexpress
Project description:The chromatin modifying enzymes that drive the erythroid-specific transcription program are incompletely understood. Setd8 is the sole histone methyltransferase in mammals capable of generating mono-methylated histone H4 lysine 20 (H4K20me1) and is expressed at significantly higher levels in erythroid cells than any other cell- or tissue- type, suggesting that Setd8 has an erythroid-specific function. To test this hypothesis, stable knockdown of Setd8 was established in extensively self-renewing erythroblasts (ESREs), a well-characterized, non-transformed, model of erythroid maturation. Setd8 knockdown impaired erythroid maturation, characterized by a delay in hemoglobin accumulation, larger cell area, persistent kit expression, incomplete nuclear condensation, and lower rates of enucleation than control cells. Setd8 knockdown did not alter ESRE proliferation or viability, or result in accumulation of DNA damage. Global gene expression analyses following Setd8 knockdown suggests that in erythroid cells, Setd8 functions primarily as a repressor and demonstrated high levels of Gata2 expression. Setd8 occupies critical regulatory elements in the Gata2 locus, and knockdown of Setd8 resulted in loss of H4K20me1 and gain of H4 acetylation at the Gata2 1S promoter. Taken together, these results imply that Setd8 is an important regulator of erythroid maturation that works in part through repression of Gata2.
2015-04-24 | GSE62647 | GEO
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
Project description:SETD8 is a histone methyltransferase that catalyzes the monomethylation of histone H4K20. Overexpressed in cancer, several studies have suggested that it could be a potential target for treatment in certain tumors. However, there are currently very few SETD8 inhibitors, and all of them have bad pharmacological properties. Based on previously published structures of SETD8 bound to an H4K20me peptide, we have discovered a new chemical series of SETD8 inhibitors. As part of the characterization of these molecules, we conducted Thermal Proteome Profiling, aiming to discover potential additional targets as well as a better understanding of the signaling pathways that are affected by the drug.
2024-10-17 | PXD051199 | Pride
Project description:The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests 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. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7 promotes NSC reactivation by regulating Wnt signaling and cell-cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 during brain development.
| S-SCDT-EMBOR-2020-50994V1 | biostudies-other
Project description:The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests 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. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 during brain development.
| S-EPMC8024890 | biostudies-literature
Project description:The establishment and maintenance of cell type-specific transcriptional programs require an ensemble of broadly expressed chromatin remodeling and modifying enzymes. Many questions remain unanswered regarding the contributions of these enzymes to specialized genetic networks that control critical processes such as lineage commitment and cellular differentiation. We have been addressing this problem in the context of erythrocyte development driven by the transcription factor GATA-1 and its coregulator Friend of GATA-1 (FOG-1). As certain GATA-1 target genes have little to no FOG-1 requirement for expression, presumably additional coregulators can mediate GATA-1 function. Using a genetic complementation assay and RNA interference in GATA-1-null cells, we demonstrate a vital link between GATA-1 and the histone H4 lysine 20 methyltransferase PR-Set7/SetD8 (SetD8). GATA-1 selectively induced H4 monomethylated lysine 20 at repressed, but not activated, loci, and endogenous SetD8 mediated GATA-1-dependent repression of a cohort of its target genes. GATA-1 utilized different combinations of SetD8, FOG-1, and the FOG-1-interacting Nucleosome Remodeling and Deacetylase (NuRD) complex component Mi2b to repress distinct target genes. Implicating SetD8 as a context-dependent GATA-1 corepressor expands the repertoire of coregulators mediating establishment/maintenance of the erythroid cell genetic network and provides a biological framework for dissecting the cell type-specific functions of this important coregulator. We propose a coregulator matrix model in which distinct combinations of chromatin regulators are required at different GATA-1 target genes, and the unique attributes of the target loci mandate these combinations. 3 SetD8 knockdown samples were compared to 3 control samples
2013-07-24 | E-GEOD-49174 | biostudies-arrayexpress
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