USP11/LSH/CYP24A1 axis activation underlies calcium homeostasis and potentiates the resistance of colorectal cancer cells to ferroptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211866 | GEO | 2023/07/12
REPOSITORIES: GEO
Similar Datasets
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: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: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
Project description:Whole-genome single-base resolution methylcytosine map reveals profound changes that occur after Lsh deletion during embryonic development in primary WT and Lsh-/- MEFs. Lsh deletion leads to widespread decreases of CG methylation level at uniquely mapped genomic regions compared to wild type, including TSSs at protein-coding genes, and non-coding RNA genes. MethylC-Seq from Mus musculus primary MEFs.
2014-06-13 | E-GEOD-57486 | biostudies-arrayexpress
Project description:We report here differences in MNase digestibility comparing murine embryonic fibroblasts (MEFs) with and without Lsh. In the first set of samples we compare primary MEFs derived from Lsh+/+ (pMEF_WT5) or Lsh-/- (pMEF_KO6) day 13.5 gestation embryos. In a second set we compare MEFs form conditional Lsh knockout mice before (GC-OHT-NC) or after 48 hours of tamoxifen inducible cre-recombinase expression (GC-OHT-2D). In a third set we compare Lsh knockout (Lsh cko) MEFs before (IAA-0h) and after 72 hours of IAA induced proteolytical degradation of Lsh (IAA-3D). In a fourth set we compare Lsh knockout MEFs before (IAA-0h-2) and after 7 hours of IAA induced proteolytical degradation of Lsh (IAA-7h) or after 24 hours (IAA-24). Lsh depletion leads to specific changes in chromatin accessibility at potential enhancer sites.
2019-03-28 | GSE103043 | GEO
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. Analyses of DNA methylation upon expression of either wild-type or catalytically-inactive LSH in Lsh-/- mouse embryonic fibroblasts.
2016-07-21 | E-GEOD-64384 | biostudies-arrayexpress
Project description:We report here differentiated enrichment of H3K4me1 at Lsh WT and KO mouse embryonic fibroblasts (MEFs). We found a subset of differentially enriched H3K4me1 regions in Lsh KO MEFs, and they clustered at neuronal lineage genes and overlapping with known cis-regulatory elements present in brain tissue. Reprogramming of Lsh?/? MEFs into induced pluripotent stem (iPS) cells leads to increased neuronal lineage gene expression of premarked genes and enhanced differentiation potential of Lsh?/? iPS cells toward the neuronal lineage pathway compared with WT iPS cells in vitro and in vivo. The state of H3K4me1 enrichment is partially maintained in Lsh?/? iPS cells, suggesting the regions are preserved as potential enhancers. Genome-wide maps of H3K4me1 in Lsh WT and KO primary MEFs.
2014-03-25 | E-GEOD-56151 | biostudies-arrayexpress
Project description:We report here the distribution of the histone variant macroH2A in murine embryonic fibroblasts derived fom Lsh-/- embryos or Lsh+/+ embryos day 14 gestation using ChIP-seq analysis. We find that macroH2A1 and macroH2A2 deposition are reduced in the absence of Lsh in contrast to H2B deposition. The study identifies Lsh as important regulator of genome wide macroH2A deposition.
2020-08-13 | GSE142082 | 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 5′ end of genes. Furthermore, we demonstrate that loss of Lsh promotes—as well as prevents—cytosine 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 | GSE29392 | GEO