{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:48:45Z","timestamp":1774928925918,"version":"3.50.1"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"S3","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Many groups, including our own, have proposed the use of DNA methylation profiles as biomarkers for various disease states. While much research has been done identifying DNA methylation signatures in cancer vs. normal etc., we still lack sufficient knowledge of the role that differential methylation plays during normal cellular differentiation and tissue specification. We also need thorough, genome level studies to determine the meaning of methylation of individual CpG dinucleotides in terms of gene expression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In this study, we compiled unique DNA methylation signatures from normal human heart, lung, and kidney using the Illumina Infinium 27K methylation arrays and compared those to gene expression by RNA sequencing. We have identified unique signatures of global DNA methylation for human heart, kidney and liver, and showed that DNA methylation data can be used to correctly classify various tissues. It indicates that DNA methylation reflects tissue specificity and may play an important role in tissue differentiation. The integrative analysis of methylation and RNA-Seq data showed that gene methylation and its transcriptional levels were comprehensively correlated. The location of methylation markers in terms of distance to transcription start site and CpG island showed no effects on the regulation of gene expression by DNA methylation in normal tissues.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study showed that an integrative analysis of methylation array and RNA-Seq data can be utilized to discover the global regulation of gene expression by DNA methylation and suggests that DNA methylation plays an important role in normal tissue differentiation via modulation of gene expression.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-5-s3-s4","type":"journal-article","created":{"date-parts":[[2011,12,23]],"date-time":"2011-12-23T19:20:56Z","timestamp":1324668056000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["An integrative analysis of DNA methylation and RNA-Seq data for human heart, kidney and liver"],"prefix":"10.1186","volume":"5","author":[{"given":"Linglin","family":"Xie","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brent","family":"Weichel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce Ellen","family":"Ohm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2011,12,23]]},"reference":[{"key":"812_CR1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/hdy.2010.54","volume":"105","author":"ER Gibney","year":"2010","unstructured":"Gibney ER, Nolan CM: Epigenetics and gene expression. Heredity. 2010, 105: 4-13. 10.1038\/hdy.2010.54.","journal-title":"Heredity"},{"key":"812_CR2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/321209a0","volume":"321","author":"AP Bird","year":"1986","unstructured":"Bird AP: CpG-rich islands and the function of DNA methylation. Nature. 1986, 321: 209-213. 10.1038\/321209a0.","journal-title":"Nature"},{"key":"812_CR3","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1126\/science.1111098","volume":"187","author":"R Holliday","year":"1975","unstructured":"Holliday R, Pugh JE: DNA modification mechanisms and gene activity during development. Science. 1975, 187: 226-232. 10.1126\/science.1111098.","journal-title":"Science"},{"key":"812_CR4","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/0092-8674(87)90330-8","volume":"50","author":"JL Swain","year":"1987","unstructured":"Swain JL, Stewart TA, Leder P: Parental legacy determines methylation and expression of an autosomal transgene: a molecular mechanism for parental imprinting. Cell. 1987, 50: 719-727. 10.1016\/0092-8674(87)90330-8.","journal-title":"Cell"},{"key":"812_CR5","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00439-011-1007-8","volume":"130","author":"AM Cotton","year":"2011","unstructured":"Cotton AM, Lam L, Affleck JG, Wilson IM, Penaherrera MS: Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum Genet. 2011, 130: 187-201. 10.1007\/s00439-011-1007-8.","journal-title":"Hum Genet"},{"key":"812_CR6","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1159\/000130315","volume":"14","author":"AD Riggs","year":"1975","unstructured":"Riggs AD: X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet. 1975, 14: 9-25. 10.1159\/000130315.","journal-title":"Cytogenet Cell Genet"},{"key":"812_CR7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1159\/000071569","volume":"99","author":"AD Riggs","year":"2002","unstructured":"Riggs AD: X chromosome inactivation, differentiation, and DNA methylation revisited, with a tribute to Susumu Ohno. Cytogenet Genome Res. 2002, 99: 17-24. 10.1159\/000071569.","journal-title":"Cytogenet Genome Res"},{"key":"812_CR8","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/0092-8674(92)90611-F","volume":"69","author":"E Li","year":"1992","unstructured":"Li E, Bestor TH, Jaenisch R: Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992, 69: 915-926. 10.1016\/0092-8674(92)90611-F.","journal-title":"Cell"},{"key":"812_CR9","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nature02625","volume":"429","author":"G Egger","year":"2004","unstructured":"Egger G, Liang G, Aparicio A, Jones PA: Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004, 429: 457-463. 10.1038\/nature02625.","journal-title":"Nature"},{"issue":"Spec No 1","key":"812_CR10","doi-asserted-by":"publisher","first-page":"R3","DOI":"10.1093\/hmg\/ddi110","volume":"14","author":"A Murrell","year":"2005","unstructured":"Murrell A, Rakyan VK, Beck S: From genome to epigenome. Hum Mol Genet. 2005, 14 (Spec No 1): R3-R10.","journal-title":"Hum Mol Genet"},{"issue":"Suppl","key":"812_CR11","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/ng1089","volume":"33","author":"R Jaenisch","year":"2003","unstructured":"Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003, 33 (Suppl): 245-254.","journal-title":"Nat Genet"},{"key":"812_CR12","doi-asserted-by":"publisher","first-page":"3336","DOI":"10.1073\/pnas.0408436102","volume":"102","author":"F Song","year":"2005","unstructured":"Song F, Smith JF, Kimura MT, Morrow AD, Matsuyama T: Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci USA. 2005, 102: 3336-3341. 10.1073\/pnas.0408436102.","journal-title":"Proc Natl Acad Sci USA"},{"key":"812_CR13","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.ygeno.2006.11.006","volume":"89","author":"E Kitamura","year":"2007","unstructured":"Kitamura E, Igarashi J, Morohashi A, Hida N, Oinuma T: Analysis of tissue-specific differentially methylated regions (TDMs) in humans. Genomics. 2007, 89: 326-337. 10.1016\/j.ygeno.2006.11.006.","journal-title":"Genomics"},{"key":"812_CR14","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/ng886","volume":"31","author":"BW Futscher","year":"2002","unstructured":"Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL: Role for DNA methylation in the control of cell type specific maspin expression. Nat Genet. 2002, 31: 175-179. 10.1038\/ng886.","journal-title":"Nat Genet"},{"key":"812_CR15","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/nature10229","volume":"475","author":"SR Ferron","year":"2011","unstructured":"Ferron SR, Charalambous M, Radford E, McEwen K, Wildner H: Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature. 2011, 475: 381-385. 10.1038\/nature10229.","journal-title":"Nature"},{"key":"812_CR16","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/nrg1602","volume":"6","author":"W Reik","year":"2005","unstructured":"Reik W, Lewis A: Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet. 2005, 6: 403-410.","journal-title":"Nat Rev Genet"},{"key":"812_CR17","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1002\/dvdy.21094","volume":"236","author":"JC Kiefer","year":"2007","unstructured":"Kiefer JC: Epigenetics in development. Dev Dyn. 2007, 236: 1144-1156. 10.1002\/dvdy.21094.","journal-title":"Dev Dyn"},{"key":"812_CR18","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1101\/gad.13.1.26","volume":"13","author":"CP Walsh","year":"1999","unstructured":"Walsh CP, Bestor TH: Cytosine methylation and mammalian development. Genes Dev. 1999, 13: 26-34. 10.1101\/gad.13.1.26.","journal-title":"Genes Dev"},{"key":"812_CR19","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1128\/MCB.19.1.164","volume":"19","author":"PM Warnecke","year":"1999","unstructured":"Warnecke PM, Clark SJ: DNA methylation profile of the mouse skeletal alpha-actin promoter during development and differentiation. Mol Cell Biol. 1999, 19: 164-172.","journal-title":"Mol Cell Biol"},{"key":"812_CR20","doi-asserted-by":"publisher","first-page":"e1001316","DOI":"10.1371\/journal.pgen.1001316","volume":"7","author":"AA Pai","year":"2011","unstructured":"Pai AA, Bell JT, Marioni JC, Pritchard JK, Gilad Y: A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues. PLoS Genet. 2011, 7: e1001316-10.1371\/journal.pgen.1001316.","journal-title":"PLoS Genet"},{"key":"812_CR21","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/nmeth.1226","volume":"5","author":"A Mortazavi","year":"2008","unstructured":"Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008, 5: 621-628. 10.1038\/nmeth.1226.","journal-title":"Nat Methods"},{"key":"812_CR22","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","volume":"25","author":"C Trapnell","year":"2009","unstructured":"Trapnell C, Pachter L, Salzberg SL: TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009, 25: 1105-1111. 10.1093\/bioinformatics\/btp120.","journal-title":"Bioinformatics"},{"key":"812_CR23","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/nbt.1621","volume":"28","author":"C Trapnell","year":"2010","unstructured":"Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G: Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010, 28: 511-515. 10.1038\/nbt.1621.","journal-title":"Nat Biotechnol"},{"key":"812_CR24","doi-asserted-by":"publisher","first-page":"2812","DOI":"10.1074\/jbc.M510365200","volume":"281","author":"JE Friedman","year":"2006","unstructured":"Friedman JE, Watson JA, Lam DW, Rokita SE: Iodotyrosine deiodinase is the first mammalian member of the NADH oxidase\/flavin reductase superfamily. J Biol Chem. 2006, 281: 2812-2819.","journal-title":"J Biol Chem"},{"key":"812_CR25","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1093\/ndt\/gfg089","volume":"18","author":"H Birn","year":"2003","unstructured":"Birn H, Nexo E, Christensen EI, Nielsen R: Diversity in rat tissue accumulation of vitamin B12 supports a distinct role for the kidney in vitamin B12 homeostasis. Nephrol Dial Transplant. 2003, 18: 1095-1100. 10.1093\/ndt\/gfg089.","journal-title":"Nephrol Dial Transplant"},{"key":"812_CR26","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1152\/physiolgenomics.00318.2005","volume":"27","author":"C Cerutti","year":"2006","unstructured":"Cerutti C, Kurdi M, Bricca G, Hodroj W, Paultre C: Transcriptional alterations in the left ventricle of three hypertensive rat models. Physiol Genomics. 2006, 27: 295-308. 10.1152\/physiolgenomics.00318.2005.","journal-title":"Physiol Genomics"},{"key":"812_CR27","doi-asserted-by":"publisher","first-page":"6857","DOI":"10.1093\/nar\/16.14.6857","volume":"16","author":"BJ Cox","year":"1988","unstructured":"Cox BJ, Robins DM: Tissue-specific variation in C4 and Slp gene regulation. Nucleic Acids Res. 1988, 16: 6857-6870. 10.1093\/nar\/16.14.6857.","journal-title":"Nucleic Acids Res"},{"key":"812_CR28","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1073\/pnas.92.4.1013","volume":"92","author":"S Nielsen","year":"1995","unstructured":"Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK: Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA. 1995, 92: 1013-1017. 10.1073\/pnas.92.4.1013.","journal-title":"Proc Natl Acad Sci USA"},{"key":"812_CR29","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/nrm1938","volume":"7","author":"E Meshorer","year":"2006","unstructured":"Meshorer E, Misteli T: Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol. 2006, 7: 540-546. 10.1038\/nrm1938.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"812_CR30","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/nature05918","volume":"447","author":"W Reik","year":"2007","unstructured":"Reik W: Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007, 447: 425-432. 10.1038\/nature05918.","journal-title":"Nature"},{"key":"812_CR31","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1172\/JCI200113030","volume":"108","author":"K Sakashita","year":"2001","unstructured":"Sakashita K, Koike K, Kinoshita T, Shiohara M, Kamijo T: Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. J Clin Invest. 2001, 108: 1195-1204.","journal-title":"J Clin Invest"},{"key":"812_CR32","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/0092-8674(83)90332-X","volume":"33","author":"PG Kratzer","year":"1983","unstructured":"Kratzer PG, Chapman VM, Lambert H, Evans RE, Liskay RM: Differences in the DNA of the inactive X chromosomes of fetal and extraembryonic tissues of mice. Cell. 1983, 33: 37-42. 10.1016\/0092-8674(83)90332-X.","journal-title":"Cell"},{"key":"812_CR33","doi-asserted-by":"publisher","first-page":"2042","DOI":"10.1056\/NEJMra023075","volume":"349","author":"JG Herman","year":"2003","unstructured":"Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003, 349: 2042-2054. 10.1056\/NEJMra023075.","journal-title":"N Engl J Med"},{"key":"812_CR34","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/5947","volume":"21","author":"PA Jones","year":"1999","unstructured":"Jones PA, Laird PW: Cancer epigenetics comes of age. Nat Genet. 1999, 21: 163-167. 10.1038\/5947.","journal-title":"Nat Genet"},{"key":"812_CR35","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/nrc1279","volume":"4","author":"AP Feinberg","year":"2004","unstructured":"Feinberg AP, Tycko B: The history of cancer epigenetics. Nat Rev Cancer. 2004, 4: 143-153. 10.1038\/nrc1279.","journal-title":"Nat Rev Cancer"},{"key":"812_CR36","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/nrg962","volume":"3","author":"PA Jones","year":"2002","unstructured":"Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002, 3: 415-428.","journal-title":"Nat Rev Genet"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-5-S3-S4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T17:53:56Z","timestamp":1630518836000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-5-S3-S4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12]]},"references-count":36,"journal-issue":{"issue":"S3","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["812"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-5-s3-s4","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12]]},"assertion":[{"value":"23 December 2011","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"S4"}}