CRL4DCAF8 Dependent Opposing Stability Control over Chromatin Remodeler LSH Governs the Epigenetic Dynamics in Ferroptosis
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ABSTRACT:
PROVIDER: PRJNA558561 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9900680.fastq.gz | Fastqsanger.gz | |||
| SRR9900681.fastq.gz | Fastqsanger.gz | |||
| SRR9900672.fastq.gz | Fastqsanger.gz | |||
| SRR9900682.fastq.gz | Fastqsanger.gz | |||
| SRR9900673.fastq.gz | Fastqsanger.gz |
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Project description:Despite the emerging evidence of ferroptosis implicated in diverse pathological scenarios, molecular adaptors linking its oxidative inducers and chromatin as carrier of stable epigenetic memory for its propagation remain elusive. Here, we report the identification of two WD40 proteins DCAF8 and WDR76 as substrate adaptor and molecular inhibitor respectively of the Cullin-4 RING ubiquitin ligase (CRL4) system for stability control of the chromatin remodeler LSH. Degradation analysis and CRL4-DCAF8 complex reconstitution demonstrate that CRL4DCAF8 is a bona fide E3 ligase for LSH. In contrast, WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of the holo-CRL4DCAF8-LSH complex assembly. Importantly, this opposing regulatory strategy is utilized in lipid hydroperoxide induced ferroptosis, and we identify key redox homeostasis genes significantly regulated by the DCAF8/WDR76/LSH axis through transcriptomic epistasis analysis. Such responsiveness could be attributed to increased ratio of DCAF8 over WDR76 for antagonistic LSH association accompanying ROS overproduction invoked decrease of TET-catalyzed DNA oxidation. Evaluation of epigenetic dynamics at DCAF8/WDR76/LSH-regulated gene promoters reveals linker histone H1- and LSH-associated transcriptional repression is coordinately removed in ferroptosis. Together with phenotypes driven by WDR76 and DCAF8 manipulations, these data identify DCAF8- and WDR76-governed LSH degradation as a crucial node in ferroptosis, tumorigenesis and senescence.
2021-06-09 | GSE135361 | GEO
Project description:The chromatin remodeler Lsh modulates genome-wide cytosine hydroxymethylation
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Project description:TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. While Tet proteins have been associated to epigenetic repression or activation complexes, our understanding of the molecular mechanisms involved in Tet-mediated regulation of gene transcription remains limited. Here, we showed that Tet directly interact with lymphoid-specific helicase (Lsh), a chromatin remodelling factor belonging to the ISWI family. This specific interaction seems to regulate Tet enzymatic activity since Lsh knock-out leads to a substantial reduction of 5-hydroxymethylation global level in mouse embryonic fibroblasts (MEFs) and in embryonic stem cells (ES). Whole genome sequencing of 5hmC in wild-type versus Lsh knock-out MEFs and ESCs showed that in absence of Lsh some regions of the genome gain while others loose 5hmC marks, with a weak correlation to gene expression changes . We further demonstrated that 5hmC modifications upon Lsh loss are not a direct consequence of 5mC decrease as DhMR (differentially hydroxymethylated regions) did not overlap with DMR (differentially methylated regions) underlying that these modifications occurred at different genomic loci. Altogether, our results suggest that DNA 5-hydroxymethylation and nucleosome folding are linked phenomena, highlighting novel means by which Tet proteins may influence gene regulation.
2021-01-31 | GSE110129 | GEO
Project description:Accumulative studies indicate that DNA maintenance methylation by DNMT1 is initiated by binding of UHRF1 to replication fork. However, how UHRF1 gains access to chromatin in S phase is poorly understood. Here we report that LSH, a SNF2 family chromatin remodeler, facilitates DNA methylation in somatic cells primarily by promoting DNA methylation by DNMT1. We show that knockout of LSH in various somatic cells resulted in substantial reduction of DNA methylation, whereas knockout of DNMT3A and DNMT3B only moderately reduced the level of DNA methylation. Consistent with a role in maintenance methylation, genome-wide analysis of DNA methylation revealed a widespread reduction of DNA methylation in all genomic elements in LSH null cells. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association, UHRF1-catalyzed H3 ubiquitination, and subsequent DNMT1 recruitment to replication fork. Notably, UHRF1 also enhances LSH association with replication fork. Thus, our study identifies LSH as an essential factor for maintenance methylation and provides novel insight into how LSH facilitates maintenance methylation.
2020-12-01 | GSE136931 | GEO
Project description:DNA methylation is critical for normal development and plays important roles in genome organization and transcriptional regulation. Although DNA methyltransferases have been identified, the factors that establish and contribute to genome-wide methylation patterns remain elusive. Here, we report a high-resolution cytosine methylation map of the murine genome modulated by Lsh, a chromatin remodeling family member that has previously been shown to regulate CpG methylation at repetitive sequences. We provide evidence that Lsh also controls genome-wide cytosine methylation at nonrepeat sequences and relate those changes to alterations in H4K4me3 modification and gene expression. Deletion of Lsh alters the allocation of cytosine methylation in chromosomal regions of 50 kb to 2 Mb and, in addition, leads to changes in the methylation profile at the 5â² end of genes. Furthermore, we demonstrate that loss of Lsh promotesâas well as preventsâcytosine methylation. Our data indicate that Lsh is an epigenetic modulator that is critical for normal distribution of cytosine methylation throughout the murine genome.
2011-05-19 | GSE29393 | GEO
Project description:To explore the key downstream factors for USP11 stable LSH regulation, we performed transcriptome analysis using controls, USP11 knockdown, and LSH knockdown HCT116 cells We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different cells.
2023-07-12 | GSE211866 | GEO
Project description:We conducted a proteomic interactome analysis of well-known regulators of ferroptosis, ACSL4, LPCAT3, ALOX12, ALOX15, PEBP1, NCOA4, GCH1, FSP1, DHODH, SLC7A11, GCLC, GCLM, GSS, and GPX4. Take LPCAT3 as an example, we uncovered an opposing role of its binding protein CEPT1 in suppressing ferroptosis.
2024-10-17 | PXD035146 | Pride
Project description:Opposing chromatin remodeler activities control initiation frequency and start site selection
| PRJNA474909 | ENA
Project description:DNA methylation is critical for normal development and plays important roles in genome organization and transcriptional regulation. Although DNA methyltransferases have been identified, the factors that establish and contribute to genome-wide methylation patterns remain elusive. Here, we report a high-resolution cytosine methylation map of the murine genome modulated by Lsh, a chromatin remodeling family member that has previously been shown to regulate CpG methylation at repetitive sequences. We provide evidence that Lsh also controls genome-wide cytosine methylation at nonrepeat sequences and relate those changes to alterations in H4K4me3 modification and gene expression. Deletion of Lsh alters the allocation of cytosine methylation in chromosomal regions of 50 kb to 2 Mb and, in addition, leads to changes in the methylation profile at the 5M-CM-"M-BM-^@M-BM-2 end of genes. Furthermore, we demonstrate that loss of Lsh promotesM-CM-"M-BM-^@M-BM-^Tas well as preventsM-CM-"M-BM-^@M-BM-^Tcytosine methylation. Our data indicate that Lsh is an epigenetic modulator that is critical for normal distribution of cytosine methylation throughout the murine genome. Chromatin immunoprecipitation followed by genomic sequencing was used to compare H3K4me3 modifications between wild type murine embryonal fibroblast cell lines (MEFs) and Lsh-/-MEFs.
2011-05-19 | E-GEOD-29393 | biostudies-arrayexpress
Project description:Purpose: We aimed to determine whether the expression of either wild-type or catalytically inactive LSH, carrying a single point mutation in its ATP binding site (K237Q), could restore the levels and patterns of DNA methylation in Lsh-/- mouse embryonic fibroblasts (MEFs). Methods: Lsh-/- MEFs were transduced with lentiviral particles carrying empty pMSCV vector, pMSCV-LSH-3xFLAG and pMSCV-LSH K/Q-3xFLAG, respectively. Clonal cell lines were generated and tested for LSH expression. Two independent cell lines expressing wild-type LSH and two expressing LSH K/Q were used for further analyses and comparison with wild-type MEFs and Lsh-/- MEFs carrying the empty vector. Genomic DNA was purified from all six cell lines and methylated DNA immunoprecipitation (MeDIP) was performed as described in Weber et al., 2007, Nat Genetics. MeDIP libraries were generated and sequenced on Illumina HiSeq 2000 instrument. Results and conclusions: Our experiments demonstrate that the expression of wild-type LSH, but not the catalytically inactive LSH K/Q, in Lsh-/- MEFs leads to reestablishment of DNA methylation at repetitive sequences and unique developmentally regulated loci in a cell-autonomous manner.
2016-07-21 | GSE64384 | GEO