CpG island turnover is associated with evolutionary changes in enhancer activity
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ABSTRACT:
PROVIDER: PRJNA963191 | ENA |
REPOSITORIES: ENA
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Project description:Changes in the activity of transcriptional enhancers have been shown to influence phenotypic variation across species. However, it remains challenging to identify the sequence features associated with species differences in enhancer activity. Here we assessed the contribution of orphan CpG islands (oCGIs), which are regions enriched in CpG dinucleotides that are known to recruit chromatin modifiers and components of the transcriptional machinery. We integrated oCGIs in nine mammals with previously ascertained maps of chromatin modifications across multiple tissues, and found that species-specific oCGIs significantly co-localize with species-specific histone modification peaks. We focused on one enhancer of interest (hs754) which contains an oCGI in human but not in mouse, and overlaps an H3K27ac peak in the developing human brain, but not in mouse. We generated a humanized mouse model and profiled the locus using ChIP-seq, finding increased deposition of the histone modifications H3K27ac and H3K4me3 and gained CTCF binding sites in the humanized enhancer. ChIP-seq data for H3K27me3 was also generated and was not included in the final study, but is deposited here. We also measured gene expression in the humanized mouse and did not find any changes associated with the humanized enhancer, although using the datasets described above we found that genes near enhancers with species-specific oCGIs and species-specific activity show a species bias in expression. This work identifies oCGI turnover as a mechanism affecting mammalian enhancer evolution.
2023-05-10 | GSE231307 | GEO
Project description:Genetic changes that modify the function of transcriptional enhancers have been linked to the evolution of biological diversity across species. Multiple studies have focused on the role of nucleotide substitutions, transposition, and insertions and deletions in altering enhancer function. Here we show that turnover of CpG islands (CGIs), which contribute to enhancer activation, is broadly associated with changes in enhancer activity across mammals, including humans. We integrated maps of CGIs and enhancer activity-associated histone modifications obtained from multiple tissues in nine mammalian species and found that CGI content in enhancers was strongly associated with increased histone modification levels. CGIs showed widespread turnover across species and species-specific CGIs were strongly enriched for enhancers exhibiting species-specific activity across all tissues and species we examined. Genes associated with enhancers with species-specific CGIs showed concordant biases in their expression, supporting that CGI turnover contributes to gene regulatory innovation. Our results also implicate CGI turnover in the evolution of Human Gain Enhancers (HGEs), which show increased activity in human embryonic development and may have contributed to the evolution of uniquely human traits. Using a humanized mouse model, we show that a highly conserved HGE with a large CGI absent from the mouse ortholog shows increased activity at the human CGI in the humanized mouse diencephalon. Collectively, our results point to CGI turnover as a mechanism driving gene regulatory changes potentially underlying trait evolution in mammals.
| S-EPMC10197647 | biostudies-literature
Project description:We compare the methylation status of CpG island clones by MeDIP in SW48 colon cancer cells relative to normal colon mucosa and WI38 primary fibroblasts. Keywords: ordered
2005-07-03 | GSE2653 | GEO
Project description:Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and posions Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Here we show that both anthracyclines and Topoisomerase II poison cause enhanced DNA double-strand breaks around CpG island promoters of active genes genome-wide. We propose that torsion-based enhancement of nucleosome turnover exposes promoter DNA, ultimately causing DNA breaks around promoters that contributes to cell killing.
2015-01-31 | GSE62927 | GEO
Project description:We compare the methylation status of CpG island clones by MeDIP in SW48 colon cancer cells relative to normal colon mucosa and WI38 primary fibroblasts.
2010-06-09 | E-GEOD-2653 | biostudies-arrayexpress
Project description:Integration of synthetic CpG Free DNA induces de novo DNAme in the flanking CpG island. Cellular differentiation requires global changes to DNA methylation (DNAme), where it functions to regulate transcription factor and chromatin remodeling activity, and genome interpretation. Here, we describe a simple DNAme engineering approach in pluripotent stem cells (PSCs), extending across large stretches of CpG dense “islands (CGIs).” Integration of synthetic CpG free single-stranded DNA (ssDNA) induces a target CpG Island Methylation Response (CIMR) in multiple PSC lines, Nt2d1 embryonal carcinoma cells, and mouse PSCs, but not in highly methylated CpG Island Methylator Phenotype (CIMP) positive cancer lines. CIMR DNAme at MLH1 spans the CGI, is robustly maintained throughout cellular differentiation, suppresses target gene activity, and sensitizes derived cardiomyocytes and thymic epithelial cells to the chemotherapy cisplatin. Additional CIMR DNAme is reported on at TP53 and ONECUT1 CGIs. Collectively, this new resource enables total CpG Island DNAme engineering in pluripotency and the genesis of novel epigenetic models of development and disease
2023-06-21 | GSE210680 | GEO
Project description:Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and posions Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Here we show that both anthracyclines and Topoisomerase II poison cause enhanced DNA double-strand breaks around CpG island promoters of active genes genome-wide. We propose that torsion-based enhancement of nucleosome turnover exposes promoter DNA, ultimately causing DNA breaks around promoters that contributes to cell killing. We have analyzed mouse squamous cell carcinoma cells treated with doxorubicin, aclarubicin and etoposide. The direct in situ Breaks Labeling, Enrichment on Streptavidin (BLESS, PMID 23503052) method was used for mapping DNA double-strand breaks genome-wide.
2015-01-31 | E-GEOD-62927 | biostudies-arrayexpress
Project description:Astrocytomas are common and lethal human brain tumors. Here, we have analyzed the methylation status of over 28,000 CpG islands and 18,000 promoters in normal human brain and in astrocytomas of various grades using the methylated-CpG island recovery assay (MIRA). We identified six to seven thousand methylated CpG islands in normal human brain. ~5% of the promoter-associated CpG islands in normal brain are methylated. Promoter CpG island methylation is inversely and intragenic methylation is directly correlated with gene expression levels in brain tissue. In astrocytomas, several hundred CpG islands undergo specific hypermethylation relative to normal brain with 428 methylation peaks common to more than 25% of the tumors. Genes involved in brain development and neuronal differentiation, such as POU4F3, GDNF, OTX2, NEFM, CNTN4, OTP, SIM1, FYN, EN1, CHAT, GSX2, NKX6-1, RAX, PAX6, DLX2, were strongly enriched among genes frequently methylated in tumors. There was an overrepresentation of homeobox genes and 31% of the most commonly methylated genes represent targets of the Polycomb complex. We identified several chromosomal loci in which many (sometimes more than 20) consecutive CpG islands were hypermethylated in tumors. Seven of such loci were near homeobox genes, including the HOXC and HOXD clusters, and the BARHL2, DLX1, and PITX2 genes. Two other clusters of hypermethylated islands were at sequences of recent gene duplication events. Our analysis offers mechanistic insights into brain neoplasia suggesting that methylation of genes involved in neuronal differentiation, perhaps in cooperation with other oncogenic events, may shift the balance from regulated differentiation towards gliomagenesis.
2010-01-01 | GSE19391 | GEO
Project description:Astrocytomas are common and lethal human brain tumors. Here, we have analyzed the methylation status of over 28,000 CpG islands and 18,000 promoters in normal human brain and in astrocytomas of various grades using the methylated-CpG island recovery assay (MIRA). We identified six to seven thousand methylated CpG islands in normal human brain. ~5% of the promoter-associated CpG islands in normal brain are methylated. Promoter CpG island methylation is inversely and intragenic methylation is directly correlated with gene expression levels in brain tissue. In astrocytomas, several hundred CpG islands undergo specific hypermethylation relative to normal brain with 428 methylation peaks common to more than 25% of the tumors. Genes involved in brain development and neuronal differentiation, such as POU4F3, GDNF, OTX2, NEFM, CNTN4, OTP, SIM1, FYN, EN1, CHAT, GSX2, NKX6-1, RAX, PAX6, DLX2, were strongly enriched among genes frequently methylated in tumors. There was an overrepresentation of homeobox genes and 31% of the most commonly methylated genes represent targets of the Polycomb complex. We identified several chromosomal loci in which many (sometimes more than 20) consecutive CpG islands were hypermethylated in tumors. Seven of such loci were near homeobox genes, including the HOXC and HOXD clusters, and the BARHL2, DLX1, and PITX2 genes. Two other clusters of hypermethylated islands were at sequences of recent gene duplication events. Our analysis offers mechanistic insights into brain neoplasia suggesting that methylation of genes involved in neuronal differentiation, perhaps in cooperation with other oncogenic events, may shift the balance from regulated differentiation towards gliomagenesis. Comparison of methylation patterns of 30 astrocytomas and 6 controls
2010-05-16 | E-GEOD-19391 | biostudies-arrayexpress
Project description:Tissue-specific methylation patterns suggest a role for CpG island methylation in differentiation and cell-type-specific gene regulation. We have profiled CpG island methylation in different cells of the immune cell lineage to investigate this role. MBD-affinity purification combined with next generation sequencing was used to analyse CpG island methylation in dendritic cells, B cells, Th1, Th2 and naïve T cells. ChIP-seq was carried out to determine RNA polymerase II binding sites in these cell types and this was compared to the methylation profiles obtained. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ Abstract: We have profiled CpG island methylation in various immune system cell types and related this to gene expression in these cells.
2011-11-10 | E-ERAD-27 | biostudies-arrayexpress