Molecular properties of epimutation hotspots
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ABSTRACT:
PROVIDER: PRJNA740019 | ENA |
REPOSITORIES: ENA
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Project description:Mistakes in the maintenance of CG methylation is a source of heritable epimutations in plants. Multigenerational surveys indicate that the rate of these stochastic events varies substantially across the genome, with some regions harboring localized “epimutation hotspots”. Using Arabidopsis as a model, we show that epimutation hotspots are indexed by a specific set of chromatin states (CS) that map to sub-regions of gene body methylation genes. Although these regions comprise only ~12% of all CGs in the genome, they account for ~63% of all epimutation events per unit time. Molecular profiling revealed that these regions contain unique sequence features, harbor steady-state intermediate methylation levels, and act as putative targets of antagonistic DNA methylation pathways. We further demonstrate that experimentally-induced shifts in steady-state methylation in these hotspot regions are sufficient to significantly alter local epimutation intensities. Our work thus lays foundation for dissecting the molecular mechanisms of epimutation hotspots in plants.
2021-12-02 | GSE178684 | GEO
Project description:Mutations in LMNA, encoding Lamin A/C, lead to a variety of diseases known as laminopathies that include dilated cardiomyopathy (DCM). The role of epigenetic mechanisms. such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of patient-specific LMNA mutations on DNA methylation is unknown. To explore the role of DNA methylation in the context of unique LMNA mutations, we performed reduced representation bisulfite sequencing (RRBS) on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations. Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in laminopathies. These DMRs, in combination with transcriptome-wide expression data and Lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located near redistributed LADs. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of disease-associated genes dysregulated in LMNA mutated cells was uncovered, potentially due to aberrant methylation changes. In conclusion, the use of in vitro culture models of patient-derived cells and differential methylation analysis enabled the identification of epimutation hotspots and dysregulated genes, consistent with a Lamin A/C mutation-specific epigenetic disease mechanism that arose in somatic and early-developmental cell stages.
2021-07-20 | GSE164365 | GEO
Project description:DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies
| PRJNA690116 | ENA
Project description:Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem: c.-27C>A located near the transcription initiation site and c.85G>T. The c.-27C>A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation. Five members of a three-generation Caucasian Lynch syndrome family with an autosomal dominant MLH1 epimutation linked to a single nucleotide variant (c.-27C>A) within the MLH1 5'UTR were examined for copy number variations and retention of heterozygosity on chromosome 3. These five carriers of constitutional MLH1 methylation and the c.-27C>A variant were compared with 300 healthy Caucasian controls from the Wellcome Trust Case Control Consortium using three algorithms (QuantiSNP, PennCNV, COKGEN) to detect any copy number variants. The five family members studied were female (the proband II5, her affected mother I1, and three asymptomatic relatives II2, II4 and III2) are labeled according to the pedigree in Figure 3 of the associated publication (Hitchins et al., Cancer Cell, 2011). The supplementary file 'GSE30348_gw6.lrr_baf.txt' contains log R ratio and B-allele frequency values in a tab-delimited format with one marker per row.
2011-07-01 | E-GEOD-30348 | biostudies-arrayexpress
Project description:Using a mouse model of engineered p16 promoter hypermethylation (p16cis/cis), we found that p16 epimutation cooperates with mutant Apc to promote colon cancer development. Therefore, we performed RNA-seq analysis to identify genes regulated by p16 epimutation that contribute to intestinal carcinogenesis.
2023-08-02 | GSE213566 | GEO
Project description:Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem: c.-27C>A located near the transcription initiation site and c.85G>T. The c.-27C>A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
2011-07-01 | GSE30348 | GEO
Project description:Meiotic recombination, crucial for proper chromosome segregation and genome evolution, is initiated by programmed DNA double-strand breaks (DSBs) in budding and fission yeasts and likely all sexually reproducing species. In fission yeast, DSBs occur up to several hundred times more frequently at special sites, called hotspots, than in other regions of the genome. What distinguishes hotspots from cold regions is a major unsolved problem, although transcription factors determine some hotspots. We report here the discovery that three coiled-coil proteins -- Rec25, Rec27, and Mug20 -- bind essentially all hotspots with unprecedented, high specificity even without DSB formation. These small proteins are components of linear elements, are related to synaptonemal complex proteins, and are essential for nearly all DSBs at most hotspots. Our results indicate that these hotspot determinants activate or stabilize the DSB-forming protein Rec12 (Spo11 homolog) rather than promote its binding to hotspots. We propose here a new paradigm for hotspot determination and crossover control by linear element proteins.
2012-12-26 | GSE43121 | GEO
Project description:Meiotic recombination, crucial for proper chromosome segregation and genome evolution, is initiated by programmed DNA double-strand breaks (DSBs) in budding and fission yeasts and likely all sexually reproducing species. In fission yeast, DSBs occur up to several hundred times more frequently at special sites, called hotspots, than in other regions of the genome. What distinguishes hotspots from cold regions is a major unsolved problem, although transcription factors determine some hotspots. We report here the discovery that three coiled-coil proteins -- Rec25, Rec27, and Mug20 -- bind essentially all hotspots with unprecedented, high specificity even without DSB formation. These small proteins are components of linear elements, are related to synaptonemal complex proteins, and are essential for nearly all DSBs at most hotspots. Our results indicate that these hotspot determinants activate or stabilize the DSB-forming protein Rec12 (Spo11 homolog) rather than promote its binding to hotspots. We propose here a new paradigm for hotspot determination and crossover control by linear element proteins.
2012-12-26 | GSE43118 | GEO
Project description:Prophage-encoded hotspots of anti-phage systems
| PRJEB47940 | ENA
Project description:Here we have used a combination of advanced proteomics and genomics approaches to investigate the extent and mechanisms of transcription factor cross-talk at genomic hotspots. We identify ~12,000 transcription factor hotspots in the early phase of adipogenesis, and we find evidence of both simultaneous and sequential binding of transcription factors at these regions. We demonstrate for the first time that hotspots are highly enriched in large super-enhancer regions and that these drive the early adipogenic reprogramming of gene expression. Our results indicate that cooperativity between transcription factors at the level of hotspots as well as super-enhancers is very important for enhancer activity and transcriptional reprogramming. Thus, hotspots and super-enhancers constitute important regulatory hubs integrating external stimuli on chromatin.
2014-04-17 | GSE56872 | GEO