Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Kmt5a Controls Hepatic Metabolic Pathways by Facilitating RNA Pol II Release from Promoter-Proximal Regions

ABSTRACT: H4K20 monomethylation maintains genome integrity by regulating proper mitotic condensation, DNA damage response and replication licensing. Here we show that in non-dividing hepatic cells H4K20Me1 is specifically enriched in the gene bodies of active genes and dynamically regulated by the antagonistic action of PR-Set7 methylase and Phf8 demethylase. In liver-specific PR-Set7-deficient mice, reduced H4K20Me1 levels primarily affected RNAPII release from promoter-proximal regions. Glucose and fatty acid metabolic genes were highly sensitive to impaired RNAPII release. Downregulation of glycolytic genes resulted in an energy starvation condition partially compensated by AMPK activation and increased mitochondrial activity. This metabolic reprogramming generated a normoglycemic, but highly sensitized state, which upon different metabolic stress conditions, quickly aggravated into a senescent phenotype initiated by ROS overproduction and oxidative DNA damage. The results illustrate how defects in the general process of RNAPII transition into elongation phase can trigger specific metabolic changes, which lead to genome instability.

ORGANISM(S): Mus musculus

PROVIDER: GSE97338 | GEO | 2017/07/27

SECONDARY ACCESSION(S): PRJNA381445

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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

ChIP_Seq analysis in cultured hTSCs

Project description:To detect the direct target genes of H4K20me1, H4K20me3, and H3K36me3 in hTSCs, hTSCs are collected and subjected to ChIP-Seq. After aligned to human hg38 by HISAT2, peaks are called by MACS2. Our results show that methylation of H4K20 mediated by PR-SET7 as the key regulator of hTSCs, indicating the essential role of PR-SET7. This ChIP-Seq data provides fundamental information for our further physiological study of PR-SET7.

2023-06-28 | GSE196221 | GEO

ChIP_Seq analysis in cultured mTSC cells with or without Dox

Project description:To detect the direct target genes of H4K20me1, H4K20me3, and H3K4me3 in mTSCs, mTSCs with or without Dox are collected and subjected to ChIP-Seq. After aligned to mouse mm10 by HISAT2, peaks are called by MACS2. Our results show that methylation of H4K20 mediated by Pr-set7 as the key regulator of mTSCs, indicating the essential role of Pr-set7. This ChIP-Seq data provides fundamental information for our further physiological study of Pr-set7.

2023-06-28 | GSE196222 | 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

Effect of SETD8/PR-Set7 knockdown on gene expression profiles in human fibroblasts

Project description:Cellular senescence is an ireversible growth arrest with alterd metabolic potentials including DNA, RNA and protein dynamics. We found that loss of the SETD8/PR-Set7 methyltransferase, which catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1), induces senescence in human fibroblasts. To investigate the role of SETD8 in cellular senescence, we performed a microarray-based transcriptomic analysis in SETD8-knockdown cells. Our results demonstrate that SETD8 links the epigenomic gene regulation to senescence-associated metabolic remodeling.

2017-03-30 | GSE86545 | GEO

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

The mental retardation gene PHF8 mediates histone H4K20/H3K9 demethylation and regulates zebrafish brain apoptosis and craniofacial development: ChIP-Seq analysis

Project description:PHF8 (PHD Finger 8) mutations have been found in patients with X-linked mental retardation (XLMR) and craniofacial deformities. Here we identify PHF8 as the first enzyme that mediates demethylation of mono-methylated histone H4 lysine (K) 20 (H4K20me1), with additional activities towards H3K9me2/1 and H3K27me2. Patient mutations significantly compromise the demethylase activity, indicating functional importance. ChIP-seq identified PHF8 near the transcription start sites (TSS) of over 7000 target genes as well as in gene bodies and intergenic regions. PHF8 depletion resulted in up-regulation of H4K20me1 and H3K9me1 at the TSS-associated sites, and H3K9me2 in the gene bodies and intergenic regions, respectively, demonstrating differential substrate specificities at different target genomic locations. PHF8 depletion at the TSS results in decreased target gene expression, which is coincident with increased occupancy of the protein L3MBTL1 previously shown to induce chromatin compaction via binding to lower methyl states including H4K20me1 and H3K9me1. HeLa cells stably expressing control and PHF8 shRNA were used to profile the histone modifications including H4K20me1, H3K9me1 and 2 by ChIP-seq. For PHF8 ChIP-seq, chromatin was obtained by formaldehyde cross-link and sonication. For chIP-seq of Histone modifcation, chromatin was prepared by MNase digestion to obtain mono-nucleosomes.

2010-07-14 | E-GEOD-21108 | biostudies-arrayexpress

PHF8 mediates histone demethylation events in cell cycle progression [ChIP-Seq]

Project description:While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here, we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while utilizing multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1/S transition in conjunction with E2F1, HCF-1 and Set1A, at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the Condensin II loading process. Accordingly, the HEAT repeat clusters in two non-SMC Condensin II subunits, N-CAPD3 and N-CAPG2, are capable of recognizing H4K20me1, and ChIP-seq. analysis demonstrate a significant overlap of Condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression. unsynchronized HeLa cells were used to profile H3K4me2 and E2F1; unsynchronized or G1 or G1/S synchronized HeLa cells were used to profile PHF8; M phase synchronized HeLa cells were used to profile SMC4 and H4K20me1

2010-09-01 | E-GEOD-22478 | biostudies-arrayexpress

PHF8 mediates histone demethylation events in cell cycle progression [expression]

Project description:While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here, we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while utilizing multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1/S transition in conjunction with E2F1, HCF-1 and Set1A, at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the Condensin II loading process. Accordingly, the HEAT repeat clusters in two non-SMC Condensin II subunits, N-CAPD3 and N-CAPG2, are capable of recognizing H4K20me1, and ChIP-seq. analysis demonstrate a significant overlap of Condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression. Keywords: Expression profiling by array HeLa cells were transfected with either control or PHF8 siRNAs. Experiments were performed in biological duplicates. RNA were extracted and sujected to microarray analysis.

2010-09-01 | E-GEOD-22477 | biostudies-arrayexpress

The mental retardation gene PHF8 mediates histone H4K20/H3K9 demethylation and regulates zebrafish brain apoptosis and craniofacial development: expression analysis

Project description:PHF8 (PHD Finger 8) mutations have been found in patients with X-linked mental retardation (XLMR) and craniofacial deformities. Here we identify PHF8 as the first enzyme that mediates demethylation of mono-methylated histone H4 lysine (K) 20 (H4K20me1), with additional activities towards H3K9me2/1 and H3K27me2. Patient mutations significantly compromise the demethylase activity, indicating functional importance. ChIP-seq identified PHF8 near the transcription start sites (TSS) of over 7000 target genes as well as in gene bodies and intergenic regions. PHF8 depletion resulted in up-regulation of H4K20me1 and H3K9me1 at the TSS-associated sites, and H3K9me2 in the gene bodies and intergenic regions, respectively, demonstrating differential substrate specificities at different target genomic locations. PHF8 depletion at the TSS results in decreased target gene expression, which is coincident with increased occupancy of the protein L3MBTL1 previously shown to induce chromatin compaction via binding to lower methyl states including H4K20me1 and H3K9me1. PHF8 RNAi and control RNAi stable HeLa cell lines were established. RNA were isolated from triplicate cell cultures. RNAs were subject to microarray expression analysis. Hybridizations were performed in duplicate.

2010-07-14 | E-GEOD-21555 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data