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PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1

ABSTRACT: PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1

PROVIDER: PRJNA823674 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18643700_1.fastq.gz	Fastqsanger.gz
	SRR18643700_2.fastq.gz	Fastqsanger.gz
	SRR18643701_1.fastq.gz	Fastqsanger.gz
	SRR18643701_2.fastq.gz	Fastqsanger.gz
	SRR18643702_1.fastq.gz	Fastqsanger.gz

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PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1.

Project description:Phosphatidylinositol-5-phosphate (PtdIns5P)-4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4,5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localisation. Here, we unveil the role of PIP4K2B as a mechanoresponsive enzyme. PIP4K2B protein level strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to softness, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells.

| S-EPMC10015053 | biostudies-literature

PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1

Project description:Phosphatidylinositol-5-phosphate (PtdIns5P)-4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4,5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localization. Here, we unveil the role for PIP4K2B as mechanosensor. PIP4K2B protein level, indeed, strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to soft, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells.

2023-02-11 | GSE200206 | GEO

Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage

Project description:Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage

| PRJNA600874 | ENA

Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage.

Project description:Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.

| S-EPMC7237863 | biostudies-literature

Histone ubiquitination-methylation crosstalk involving UHRF1 and SUV39H1/2 reinforces heterochromatin states in response to DNA hypomethylation

Project description:Histone H3 mono-ubiquitination, catalyzed by the RING E3 ubiquitin ligase UHRF1, is appreciated as a docking site for DNMT1 during DNA replication to facilitate DNA methylation maintenance. Its functions beyond this are unknown. Here, we identify simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/2-dependent H3K9me3 as prominent epigenetic alterations accompanying DNA hypomethylation induced by DNMT1 inhibition. Integrative epigenomics analyses reveal that transient accumulation of hemi-methylated DNA, resulting from incomplete DNA methylation maintenance, stimulates UHRF1-dependent H3K18ub at CpG islands that nucleates new domains of H3K9me3 and impedes PRC2 activity in these genomic regions. Notably, H3K18ub enhances the methyltransferase activity of SUV39H1/2, leading to increased H3K9me3 at these CpG island promoters. Blocking H3K18ub-dependent SUV39H1/2 activity enhances the efficacy of DNMT1 inhibitors. Collectively, these findings reveal a novel histone ubiquitination-methylation crosstalk mechanism that reinforces heterochromatin states in the absence of DNA methylation and proposes new strategies for improving cancer epigenetic therapy.

2024-12-02 | PXD049993 | Pride

Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage

Project description:RNA and H3K9me3 ChIP sequencing data of normal human neonatal keratinocytes subjected to 40% uniaxial cyclic stretch

2020-05-11 | GSE143519 | GEO

Gene expression profiles of uhrf1 mutant zebrafish

Project description:UHRF1 (Ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication, is essential for maintaining DNA methylation patterns during cell division and is suggested to direct additional repressive epigenetic marks. Uhrf1 mutation in zebrafish results in multiple embryonic defects including failed hepatic outgrowth, but the epigenetic basis of these phenotypes is not known. We find that DNA methylation is the only epigenetic mark that is depleted in uhrf1 mutants and make the surprising finding that despite the reduced organ size in uhrf1 mutants, genes regulating DNA replication and S-phase progression were highly upregulated. Further, there is a striking increase in BrdU incorporation in uhrf1 mutant cells, and they retained BrdU labeling over several days, indicating they are arrested in S-phase. Moreover, some of the label retaining nuclei co-localized with TUNEL positive nuclei, suggesting that arrested cells are responsible for apoptosis. Importantly, dnmt1 mutation phenocopies the S-phase arrest and hepatic outgrowth defects in uhrf1 mutants and Dnmt1 knock-down enhances the uhrf1 hepatic phenotype. Together, these data indicate that DNA hypomethylation is sufficient to generate the uhrf1 mutant phenotype by promoting an S-phase arrest. We thus propose that cell cycle arrest is a mechanism to restrict propagation of epigenetically deranged cells during embryogenesis. Genome-wide expression profiling was performed on 2 uhrf1 mutant and 2 wildtype zebrafish larvae (120 hours post fertilization) by using Zebrafish Genome Array (Affymetrix) according to manufacturer's instruction.

2015-02-09 | E-GEOD-55339 | biostudies-arrayexpress

Elucidating the role of polygalacturonase genes in strawberry fruit softening

Project description:The aim of this study was to determine the role of genes encoding polygalacturonases in strawberry fruit softening. To this purpose, several transgenic lines, cv. Chandler, were generated: plants with PG genes FaPG1 or FaPG2 downregulated, alone or in combination, by antisense transformation. Plants were grown in a confined greenhouse and fruits were harvested at the stage of full ripeness (100% of fruit surface red). The results obtained indicate that the silencing of these genes reduced fruit softening at similar level but there is not a sinergistic effect on fruit firmness.

2021-01-21 | E-MTAB-8736 | biostudies-arrayexpress

UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [epic_methyl]

Project description:Methylation array was performed to understand the role of UHRF1 in DNA methylation in KRAS mutant lung cancer cell lines. Knock-down of UHRF1 leads to significant changes in global DNA methylation in both cell lines.

2023-05-15 | GSE198446 | GEO

Expression data from HeLa cell lines stably expressing shRNA targeting ctrl or UHRF1

Project description:We used microarrays to explore the expression profile from cells expressing wild type and UHRF1 S674A mutant. HeLa cells expressing UHRF1 WT and S674A mutant showed similar gene expression pattern without significant affecting the transcription of DNA repari genes. UHRF1 was depleted in HeLa cells by shRNA treatment. Total RNA was purified and used to determine the global gene transcription profiles by microarray assays. The UHRF1-related genes expression profiles were compared among control cells, UHRF1-depleted cells, UHRF1 WT reconstituting cells and UHRF1 S674A mutant reconstituting cells.

2016-01-05 | E-GEOD-73751 | biostudies-arrayexpress

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