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Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys.

ABSTRACT: Previous studies showed that the majority of developmental genes are devoid of DNA methylation at promoters even when they are repressed. Such hypomethylated regions at developmental genes are unusually large and extend well beyond proximal promoters, forming DNA methylation valleys (DMVs) or DNA methylation canyons. However, it remains elusive how most developmental genes can evade DNA methylation regardless of their transcriptional states.We show that DMVs are hypomethylated in development and are highly conserved across vertebrates. Importantly, DMVs are hotspots of regulatory regions for key developmental genes and show low levels of deamination mutation rates. By analyzing a panel of DNA methylomes from mouse tissues, we identify a subset of DMVs that are dynamically methylated. These DMVs are strongly enriched for Polycomb-deposited H3K27me3 when the associated genes are silenced, and surprisingly show elevated DNA methylation upon gene activation. 4C-seq analyses indicates that Polycomb-bound DMVs form insulated and self-interacting chromatin domains. Further investigations show that DNA hypomethylation is better correlated with the binding of Polycomb than with H3K27me3. In support of a role of Polycomb in DMV hypomethylation, we observe aberrant methylation in DMVs in mouse embryonic stem cells deficient in the EED protein. Finally, we show that Polycomb regulates hypomethylation of DMVs likely through ten-eleven translocation (TET) proteins.We show that Polycomb promotes the hypomethylation of DMVs near key developmental genes. These data reveal a delicate interplay between histone modifiers and DNA methylation, which contributes to their division at distinct gene targets, allowing lineage-specifying genes to largely maintain DNA methylation-free at regulatory elements.

SUBMITTER: Li Y

PROVIDER: S-EPMC5806489 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys.

Li Yuanyuan Y Zheng Hui H Wang Qiujun Q Zhou Chen C Wei Lei L Liu Xuehui X Zhang Wenhao W Zhang Yu Y Du Zhenhai Z Wang Xiaowo X Xie Wei W

Genome biology 20180208 1

<h4>Background</h4>Previous studies showed that the majority of developmental genes are devoid of DNA methylation at promoters even when they are repressed. Such hypomethylated regions at developmental genes are unusually large and extend well beyond proximal promoters, forming DNA methylation valleys (DMVs) or DNA methylation canyons. However, it remains elusive how most developmental genes can evade DNA methylation regardless of their transcriptional states.<h4>Results</h4>We show that DMVs ar ...[more]

PMID: 29422066

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Project description:BackgroundWool fibers are valuable materials for textile industry. Typical wool fibers are divided into medullated and non-medullated types, with the former generated from primary wool follicles and the latter by either primary or secondary wool follicles. The medullated wool is a common wool type in the ancestors of fine wool sheep before breeding. The fine wool sheep have a non-medullated coat. However, the critical period determining the type of wool follicles is the embryonic stage, which limits the phenotypic observation and variant contrast, making both selection and studies of wool type variation fairly difficult.ResultsDuring the breeding of a modern fine (MF) wool sheep population with multiple-ovulation and embryo transfer technique, we serendipitously discovered lambs with ancestral-like coarse (ALC) wool. Whole-genome resequencing confirmed ALC wool lambs as a variant type from the MF wool population. We mapped the significantly associated methylation locus on chromosome 4 by using whole genome bisulfite sequencing signals, and in turn identified the SOSTDC1 gene as exons hypermethylated in ALC wool lambs compare to their half/full sibling MF wool lambs. Transcriptome sequencing found that SOSTDC1 was expressed dozens of times more in ALC wool lamb skin than that of MF and was at the top of all differentially expressed genes. An analogy with the transcriptome of coarse/fine wool breeds revealed that differentially expressed genes and enriched pathways at postnatal lamb stage in ALC/MF were highly similar to those at the embryonic stage in the former. Further experiments validated that the SOSTDC1 gene was specifically highly expressed in the nucleus of the dermal papilla of primary wool follicles.ConclusionIn this study, we conducted genome-wide differential methylation site association analysis on differential wool type trait, and located the only CpG locus that strongly associated with primary wool follicle development. Combined with transcriptome analysis, SOSTDC1 was identified as the only gene at this locus that was specifically overexpressed in the primary wool follicle stem cells of ALC wool lamb skin. The discovery of this key gene and its epigenetic regulation contributes to understanding the domestication and breeding of fine wool sheep.

Project description:BackgroundAberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression.MethodsQuantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV.ResultsSignificant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival.ConclusionsIn the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above.

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Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys.

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Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys.

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