Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells

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A targeted approach uses padlock probes and bisulfite-treated DNA, whereas an untargeted method relies on the methylation-sensitive restriction enzyme HpaII. Studies of epigenetic modifications would benefit from improved methods for high-throughput methylation profiling. We introduce two complementary approaches that use next-generation sequencing technology to detect cytosine methylation. In the first method, we designed ∼10,000 bisulfite padlock probes to profile ∼7,000 CpG locations distributed over the ENCODE pilot project regions and applied them to human B-lymphocytes, fibroblasts and induced pluripotent stem cells. This unbiased choice of targets takes advantage of existing expression and chromatin immunoprecipitation data and enabled us to observe a pattern of low promoter methylation and high gene-body methylation in highly expressed genes. 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c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Madeleine_P-Ball-Aff1-Aff2" data-author-popup="auth-Madeleine_P-Ball-Aff1-Aff2" data-author-search="Ball, Madeleine P">Madeleine P Ball</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jin_Billy-Li-Aff1-Aff2" data-author-popup="auth-Jin_Billy-Li-Aff1-Aff2" data-author-search="Li, Jin Billy" data-corresp-id="c1">Jin Billy Li<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yuan-Gao-Aff3-Aff4" data-author-popup="auth-Yuan-Gao-Aff3-Aff4" data-author-search="Gao, Yuan">Yuan Gao</a><sup class="u-js-hide"><a href="#Aff3">3</a>,<a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Je_Hyuk-Lee-Aff1-Aff2" data-author-popup="auth-Je_Hyuk-Lee-Aff1-Aff2" data-author-search="Lee, Je-Hyuk">Je-Hyuk Lee</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Emily_M-LeProust-Aff5" data-author-popup="auth-Emily_M-LeProust-Aff5" data-author-search="LeProust, Emily M">Emily M LeProust</a><sup class="u-js-hide"><a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-In_Hyun-Park-Aff6" data-author-popup="auth-In_Hyun-Park-Aff6" data-author-search="Park, In-Hyun">In-Hyun Park</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Bin-Xie-Aff3" data-author-popup="auth-Bin-Xie-Aff3" data-author-search="Xie, Bin">Bin Xie</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-George_Q-Daley-Aff6" data-author-popup="auth-George_Q-Daley-Aff6" data-author-search="Daley, George Q">George Q Daley</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 9 authors for this article" title="Show all 9 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-George_M-Church-Aff1-Aff2" data-author-popup="auth-George_M-Church-Aff1-Aff2" data-author-search="Church, George M" data-corresp-id="c2">George M Church<svg width="16" height="16" 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data-test="article-publication-year">2009</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">6687 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">831 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">16 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nbt.1533/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-mb-8 c-status-message c-status-message--boxed c-status-message--info"> <span class="c-status-message__icon"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-info-filled-medium"></use> </svg> </span> <p class="u-mt-0">A <a href="https://doi.org/10.1038/nbt0509-485b" class="relation-link" data-track="click" data-track-action="view linked article" data-track-label="link">Corrigendum</a> to this article was published on 01 May 2009</p> </div> <div class="u-mb-8 c-status-message c-status-message--boxed c-status-message--info"> <span class="c-status-message__icon"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-info-filled-medium"></use> </svg> </span> <p class="u-mt-0">This article has been <a href="#change-history">updated</a></p> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs2" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs2">Abstract</h2><div class="c-article-section__content" id="Abs2-content"><p>Studies of epigenetic modifications would benefit from improved methods for high-throughput methylation profiling. We introduce two complementary approaches that use next-generation sequencing technology to detect cytosine methylation. In the first method, we designed <span class="stix">∼</span>10,000 bisulfite padlock probes to profile <span class="stix">∼</span>7,000 CpG locations distributed over the ENCODE pilot project regions and applied them to human B-lymphocytes, fibroblasts and induced pluripotent stem cells. This unbiased choice of targets takes advantage of existing expression and chromatin immunoprecipitation data and enabled us to observe a pattern of low promoter methylation and high gene-body methylation in highly expressed genes. The second method, methyl-sensitive cut counting, generated nontargeted genome-scale data for <span class="stix">∼</span>1.4 million <i>Hpa</i>II sites in the DNA of B-lymphocytes and confirmed that gene-body methylation in highly expressed genes is a consistent phenomenon throughout the human genome. 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density and methylation in genes with different levels of expression.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnbt.1533/MediaObjects/41587_2009_Article_BFnbt1533_Fig4_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnbt.1533/MediaObjects/41587_2009_Article_BFnbt1533_Fig4_HTML.jpg" alt="" loading="lazy" width="312" height="72"></picture></div></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5: Methylation profiles of individual genes.</b></figcaption><div class="c-article-section__figure-content"><div 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id="accession-codes-content"> <h3 class="c-article__sub-heading">Accessions</h3> <h4 class="c-article__sub-heading c-article__sub-heading--small">GenBank/EMBL/DDBJ</h4><ul class="c-article-data-availability-list u-list-reset"> <li class="c-article-data-availability-list__item"> <p> <a href="http://www.ncbi.nlm.nih.gov/nuccore/?term=SRA008183">SRA008183</a> </p> </li> </ul> </div></div></section><section data-title="Change history"><div class="c-article-section" id="change-history-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="change-history">Change history</h2><div class="c-article-section__content" id="change-history-content"><ul class="c-article-change-list"><li class="c-article-change-list__item u-mb-24" id="chg1"><ins datetime="2009-05-08"><h3 class="c-article-change-list__heading u-h3 u-pr-8 u-display-inline">08 May 2009</h3><div class="c-article-change-list__details"><p>In the version of this article initially published, the second affilliation for Yuan Gao was omitted: Department of Computer Science, Virginia Commonwealth University, Richmond, Virginia, USA. The affiliation has been added to the HTML and PDF versions of the article.</p></div></ins></li></ul></div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1"><p class="c-article-references__text" id="ref-CR1">Suzuki, M.M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. <i>Nat. Rev. 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This work was supported by the NHGRI-Centers of Excellence in Genomic Science (to G.M.C.).</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><span class="c-article-author-information__subtitle u-visually-hidden" id="author-notes">Author notes</span><ol class="c-article-author-information__list"><li class="c-article-author-information__item" id="na1"><p>Madeleine P Ball and Jin Billy Li: These authors contributed equally to this work.</p></li></ol><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Genetics, Harvard Medical School, Cambridge, Massachusetts, USA</p><p class="c-article-author-affiliation__authors-list">Madeleine P Ball, Jin Billy Li, Je-Hyuk Lee & George M Church</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA</p><p class="c-article-author-affiliation__authors-list">Madeleine P Ball, Jin Billy Li, Je-Hyuk Lee & George M Church</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia, USA</p><p class="c-article-author-affiliation__authors-list">Yuan Gao & Bin Xie</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Computer Science, Virginia Commonwealth University, Richmond, Virginia, USA</p><p class="c-article-author-affiliation__authors-list">Yuan Gao</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Genomics Solution Unit, Agilent Technologies Inc., Santa Clara, California, USA</p><p class="c-article-author-affiliation__authors-list">Emily M LeProust</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department of Medicine, Division of Pediatric Hematology Oncology, Children's Hospital Boston, and Dana-Farber Cancer Institute; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Karp Family Research Building 7214, Boston, Massachusetts, USA</p><p class="c-article-author-affiliation__authors-list">In-Hyun Park & George Q Daley</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Madeleine_P-Ball-Aff1-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Madeleine P Ball</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Madeleine%20P%20Ball" class="c-article-button" data-track="click" data-track-action="author link - 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M.P.B. and J.B.L. performed experiments and data analysis. Y.G. and B.X. carried out initial Solexa sequencing. J.-H.L. helped with culturing cell lines and isolating DNA/RNA. E.M.L. synthesized the padlock oligos. I.-H.P. and G.Q.D. generated the iPS cell lines.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding authors</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:jli@genetics.med.harvard.edu">Jin Billy Li</a> or <a id="corresp-c2" href="mailto:gmc@harvard.edu">George M Church</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading">Competing interests</h3> <p>E.M.L. is an employee of Agilent Technologies. G.M.C. is involved in eight next-generation sequencing companies. M.P.B., J.B.L. and G.M.C. are named as inventors on a patent application on technologies described in this article.</p> </div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec20-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec20">Supplementary information</h2><div class="c-article-section__content" id="Sec20-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM19"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary text and figures" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnbt.1533/MediaObjects/41587_2009_BFnbt1533_MOESM19_ESM.pdf" 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2009</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2009-03-06">06 March 2009</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2009-03-29">29 March 2009</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Issue Date<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2009-04">April 2009</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span class="c-bibliographic-information__value">https://doi.org/10.1038/nbt.1533</span></p></li></ul><div data-component="share-box"><div class="c-article-share-box 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