Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues

Ludwig Institute for Cancer Research, La Jolla, California, USA.
Nature Genetics (Impact Factor: 29.35). 09/2013; 45(10). DOI: 10.1038/ng.2746
Source: PubMed


Mammalian development requires cytosine methylation, a heritable epigenetic mark of cellular memory believed to maintain a cell's unique gene expression pattern. However, it remains unclear how dynamic DNA methylation relates to cell type-specific gene expression and animal development. Here, by mapping base-resolution methylomes in 17 adult mouse tissues at shallow coverage, we identify 302,864 tissue-specific differentially methylated regions (tsDMRs) and estimate that >6.7% of the mouse genome is variably methylated. Supporting a prominent role for DNA methylation in gene regulation, most tsDMRs occur at distal cis-regulatory elements. Unexpectedly, some tsDMRs mark enhancers that are dormant in adult tissues but active in embryonic development. These 'vestigial' enhancers are hypomethylated and lack active histone modifications in adult tissues but nevertheless exhibit activity during embryonic development. Our results provide new insights into the role of DNA methylation at tissue-specific enhancers and suggest that epigenetic memory of embryonic development may be retained in adult tissues.

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    • "In addition, HNF4A and FOSL2 showed a significant downregulation of protein levels as detected by immunoblot, whereas NR3C1 showed a downregulation trend which did not reach significance (Figs 7A and EV3B, and Source data for Fig 7). These data complement recent work linking TF binding to enhancers and tissue-specific hypomethylation (Stadler et al, 2011; Hon et al, 2013; Xie et al, 2013; Ziller et al, 2013), and also downregulation of TF networks to enhancer hypermethylation (Agirre et al, 2015). Our findings suggest that the incomplete epigenetic remodeling observed for the 2,087 DMCpGs identified in iPSC-derived DAn from PD patients might be mediated by the aberrant downregulation of a network of key TFs whose deficiency could prevent their target sites to become demethylated during the differentiation from iPSCs to DAn. "
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    ABSTRACT: The epigenomic landscape of Parkinson's disease (PD) remains unknown. We performed a genomewide DNA methylation and a transcriptome studies in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) generated by cell reprogramming of somatic skin cells from patients with monogenic LRRK2-associated PD (L2PD) or sporadic PD (sPD), and healthy subjects. We observed extensive DNA methylation changes in PD DAn, and of RNA expression, which were common in L2PD and sPD. No significant methylation differences were present in parental skin cells, undifferentiated iPSCs nor iPSC-derived neural cultures not-enriched-in-DAn. These findings suggest the presence of molecular defects in PD somatic cells which manifest only upon differentiation into the DAn cells targeted in PD. The methylation profile from PD DAn, but not from controls, resembled that of neural cultures not-enriched-in-DAn indicating a failure to fully acquire the epigenetic identity own to healthy DAn in PD. The PD-associated hypermethy-lation was prominent in gene regulatory regions such as enhancers and was related to the RNA and/or protein downregulation of a network of transcription factors relevant to PD (FOXA1, NR3C1, HNF4A, and FOSL2). Using a patient-specific iPSC-based DAn model, our study provides the first evidence that epigenetic deregulation is associated with monogenic and sporadic PD.
    Full-text · Article · Oct 2015 · EMBO Molecular Medicine
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    • "Global genomic comparisons of tissue-specific DNA methylation and transcription factor (TF) chromatin immunoprecipitation sequencing (ChIP-seq) data correlated the chromatin with the methylation state (Xie et al., 2013). Thus, many tissue-specific enhancers are hypomethylated in tissues where the target genes are expressed, but are hypermethylated in tissues where the target genes are silent (Hon et al., 2013). "
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    ABSTRACT: Mammalian DNA methylation plays an essential role in development. To date, only snapshots of different mouse and human cell types have been generated, providing a static view on DNA methylation. To enable monitoring of methylation status as it changes over time, we establish a reporter of genomic methylation (RGM) that relies on a minimal imprinted gene promoter driving a fluorescent protein. We show that insertion of RGM proximal to promoter-associated CpG islands reports the gain or loss of DNA methylation. We further utilized RGM to report endogenous methylation dynamics of non-coding regulatory elements, such as the pluripotency-specific super enhancers of Sox2 and miR290. Loci-specific DNA methylation changes and their correlation with transcription were visualized during cell-state transition following differentiation of mouse embryonic stem cells and during reprogramming of somatic cells to pluripotency. RGM will allow the investigation of dynamic methylation changes during development and disease at single-cell resolution.
    Full-text · Article · Oct 2015 · Cell
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    • "In recent years, development and improvement of nextgeneration sequencing methodologies (Lander 2011) enabled genome-wide base-resolution methylomes of multiple tissues and cell types across different species (Hon et al. 2013; Smith et al. 2014; Roadmap Epigenomics Consortium et al. 2015; Schultz et al. 2015). This unprecedented increase in available data has revolutionized the field, promising to significantly enhance our understanding of the role of DNA methylation, together with other epigenetic modifications, in maintaining and regulating cell fate (Rivera and Ren 2013; Romanoski et al. 2015). "
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    ABSTRACT: DNA methylation is a broadly studied epigenetic modification that is essential for normal mammalian development. Over the years, numerous methodologies were developed trying to cope with the intrinsic challenge of reading the "second dimension" epigenetic code. The recent rapid expansion of sequencing technologies has made it possible to fully chart the methylation landscape of different cell types at single-base resolution. Surprisingly, accumulating data suggest that, in addition to the massive epigenome remodeling during early development, cell type and tissue specification is associated with high levels of DNA methylation dynamics at distal regulatory elements. However, current methods provide only a static "snapshot" of DNA methylation, thus precluding the study of real-time methylation dynamics during cell fate changes. Here we review the principles of a new approach that enables monitoring loci-specific DNA methylation dynamics at single-cell resolution. We also discuss potential applications and promises for implementing this methodology to study DNA methylation changes during development and disease.
    Full-text · Article · Oct 2015 · Cold Spring Harbor Symposia on Quantitative Biology
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