Identification of novel hyper- or hypo-methylated CpG sites and genes associated with anthracycline-induced cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA930712 | ENA |
REPOSITORIES: ENA
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2015-11-09 | E-GEOD-74789 | biostudies-arrayexpress
Project description:We describe that during early zebrafish development, DNA methylation has little influence on enhancer activity, and that hypo-methylation is a unique feature of primed enhancers, whereas active enhancers are generally hyper-methylated. Hypo-methylated enhancers (hypo-enhancers) are enriched close to important transcription factors (TFs) that act later in development, are specifically de-methylated before the mid blastula transition (MBT), and reside in a unique epigenetic environment. Finally, we demonstrate that hypo-enhancers are functionally active later in development and that they are physically associated with the transcriptional start site (TSS) of target-genes, irrespective of target-gene activity. We performed 6 different 4C-Seq experiment at two different timepoints and in adult brain.
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Project description:We report the application of MeDIP sequencing technology for high-throughput profiling of M2 and M1 phenotype U937 cells. A total of 260 differentially methylated regions (DMRs) within promotor regions were identified, with 191 hyper-methylated and 69 hypo-methylated every chromosome. These DMRs were then further examined using GO analysis, with the top10 most enriched GO terms for both the hyper- and hypo-methylation groups isolated. The processes associated with hyper-methylation included the regulation of protein processes (targeting, processing, maturation and localization) and tyrosine phosphorylation of STAT5 protein, while the hypo-methylated processes included the regulation of epithelial to mesenchymal transition, mesenchymal cell differentiation and epithelial to mesenchymal transition. When further analyzing the regulation of tyrosine STAT5 phosphorylation, three associated genes (IL-31RA, IL-3, and NF2) previous shown to be associated with tumor or cancer development were also identified, thus suggesting that hyper-methylation may be important during M2 polarization into M1 cells. The epithelial to mesenchymal transition (EMT) process has been long accepted to be associated with cancer metastasis and malignance. Herein, four genes (TGFB1I1, TWIST1, HPN, and PHLDB2) that have been previously reported to participate in cancer invasion and metastasis were hypo-methylated during the EMT process, thus suggesting that these hypo-methylation sites might be a potential therapeutic target to control cancer metastasis. Moreover, the hyper-methylation was found to be predominantly localized to membranes, including the leading edge membrane, whole membrane, endoplasmic reticulum-Golgi intermediate compartment membrane, recycling endosome membrane and ruffle membrane, whereas the hypo-methylation was predominantly localized to the cytoskeleton, cell junction and cell cortex. These findings also suggest a potential ability for epigenetic therapy due to both the membrane and cytoskeleton being feasible targets for therapeutic chemical or antibody targeting. When performing pathway enrichment analysis for the hyper-methylated genes, fatty acid biosynthesis, ubiquitin mediated proteolysis, mRNA surveillance and AMPK signaling pathways were enriched; while for the hypo-methylated genes, pathways associated with cancers, such as tight junction, VEGF signaling, cAMP signaling, proteoglycans and Ras signaling pathways were enriched during polarization from M2 to M1 cells
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Project description:We describe that during early zebrafish development, DNA methylation has little influence on enhancer activity, and that hypo-methylation is a unique feature of primed enhancers, whereas active enhancers are generally hyper-methylated. Hypo-methylated enhancers (hypo-enhancers) are enriched close to important transcription factors (TFs) that act later in development, are specifically de-methylated before the mid blastula transition (MBT), and reside in a unique epigenetic environment. Finally, we demonstrate that hypo-enhancers are functionally active later in development and that they are physically associated with the transcriptional start site (TSS) of target-genes, irrespective of target-gene activity. we analyzed 5 novel ChIP-Seq libraries where we used the following AB (H3K27ac,H3K4me1,H3K4me2 and H3K27ac) and an Atac-Seq library.
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Project description:During development and differentiation, enhancers, and not promoters are most dynamic in their DNA methylation status. However, the causal relationship between enhancer activity and methylation is not clear. Here, we describe that during early zebrafish development, enhancer activity has little influence on DNA methylation, and that hypo-methylation is a unique feature of primed enhancers, whereas active enhancers are hyper-methylated. Hypo-methylated enhancers (hypo-enhancers) are enriched close to important transcription factors (TFs) that act later in development, are specifically de-methylated before the maternal-zygotic transition (MZT), and reside in a unique epigenetic environment. Finally, we demonstrate that hypo-enhancers are functionally active and that they are physically associated with the transcriptional start site (TSS) of target-genes, irrespective of target-gene activity. In conclusion, we demonstrate that early development in zebrafish represents a time-window characterized by non-canonical DNA methylation-enhancer relationships, including global DNA hypo-methylation of inactive enhancers and DNA hyper-methylation of active enhancers.
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