{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T14:11:22Z","timestamp":1791036682089,"version":"4.1.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Recent genomic scale survey of epigenetic states in the mammalian genomes has shown that promoters and enhancers are correlated with distinct chromatin signatures, providing a pragmatic way for systematic mapping of these regulatory elements in the genome. With rapid accumulation of chromatin modification profiles in the genome of various organisms and cell types, this chromatin based approach promises to uncover many new regulatory elements, but computational methods to effectively extract information from these datasets are still limited.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We present here a supervised learning method to predict promoters and enhancers based on their unique chromatin modification signatures. We trained Hidden Markov models (HMMs) on the histone modification data for known promoters and enhancers, and then used the trained HMMs to identify promoter or enhancer like sequences in the human genome. Using a simulated annealing (SA) procedure, we searched for the most informative combination and the optimal window size of histone marks.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Compared with the previous methods, the HMM method can capture the complex patterns of histone modifications particularly from the weak signals. Cross validation and scanning the ENCODE regions showed that our method outperforms the previous profile-based method in mapping promoters and enhancers. We also showed that including more histone marks can further boost the performance of our method. This observation suggests that the HMM is robust and is capable of integrating information from multiple histone marks. To further demonstrate the usefulness of our method, we applied it to analyzing genome wide ChIP-Seq data in three mouse cell lines and correctly predicted active and inactive promoters with positive predictive values of more than 80%. The software is available at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/nash.ucsd.edu\/chromatin.tar.gz\" ext-link-type=\"uri\">http:\/\/http:\/nash.ucsd.edu\/chromatin.tar.gz<\/jats:ext-link>.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-9-547","type":"journal-article","created":{"date-parts":[[2008,12,18]],"date-time":"2008-12-18T19:14:38Z","timestamp":1229627678000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Prediction of regulatory elements in mammalian genomes using chromatin signatures"],"prefix":"10.1186","volume":"9","author":[{"given":"Kyoung-Jae","family":"Won","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iouri","family":"Chepelev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2008,12,18]]},"reference":[{"key":"2532_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/nature01763","volume":"424","author":"M Levine","year":"2003","unstructured":"Levine M, Tjian R: Transcription regulation and animal diversity. Nature 2003, 424: 147\u201351. 10.1038\/nature01763","journal-title":"Nature"},{"key":"2532_CR2","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.cell.2007.01.033","volume":"128","author":"BE Bernstein","year":"2007","unstructured":"Bernstein BE, Meissner A, Lander ES: The mammalian epigenome. Cell 2007, 128: 669\u201381. 10.1016\/j.cell.2007.01.033","journal-title":"Cell"},{"key":"2532_CR3","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1126\/science.290.5500.2306","volume":"290","author":"B Ren","year":"2000","unstructured":"Ren B, Robert F, Wyrick JJ, Aparicio O, Jennings EG, Simon I, Zeitlinger J, Schreiber J, Hannett N, Kanin E, Volkert TL, Wilson CJ, Bell SP, Young RA: Genome-wide location and function of DNA binding proteins. Science 2000, 290: 2306\u20139. 10.1126\/science.290.5500.2306","journal-title":"Science"},{"key":"2532_CR4","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/35054095","volume":"409","author":"VR Iyer","year":"2001","unstructured":"Iyer VR, Horak CE, Scafe CS, Botstein D, Snyder M, Brown PO: Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 2001, 409: 533\u20138. 10.1038\/35054095","journal-title":"Nature"},{"key":"2532_CR5","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1101\/gr.5583007","volume":"17","author":"GM Euskirchen","year":"2007","unstructured":"Euskirchen GM, Rozowsky JS, Wei CL, Lee WH, Zhang ZD, Hartman S, Emanuelsson O, Stolc V, Weissman S, Gerstein MB, Ruan Y, Snyder M: Mapping of transcription factor binding regions in mammalian cells by ChIP: comparison of array- and sequencing-based technologies. Genome Res 2007, 17: 898\u2013909. 10.1101\/gr.5583007","journal-title":"Genome Res"},{"key":"2532_CR6","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.cell.2007.05.009","volume":"129","author":"A Barski","year":"2007","unstructured":"Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K: High-resolution profiling of histone methylations in the human genome. Cell 2007, 129: 823\u201337. 10.1016\/j.cell.2007.05.009","journal-title":"Cell"},{"key":"2532_CR7","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1126\/science.1141319","volume":"316","author":"DS Johnson","year":"2007","unstructured":"Johnson DS, Mortazavi A, Myers RM, Wold B: Genome-wide mapping of in vivo protein-DNA interactions. Science 2007, 316: 1497\u2013502. 10.1126\/science.1141319","journal-title":"Science"},{"key":"2532_CR8","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/nature06008","volume":"448","author":"TS Mikkelsen","year":"2007","unstructured":"Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O'Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE: Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007, 448: 553\u201360. 10.1038\/nature06008","journal-title":"Nature"},{"key":"2532_CR9","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1126\/science.1098119","volume":"304","author":"G Bejerano","year":"2004","unstructured":"Bejerano G, Pheasant M, Makunin I, Stephen S, Kent WJ, Mattick JS, Haussler D: Ultraconserved elements in the human genome. Science 2004, 304: 1321\u20135. 10.1126\/science.1098119","journal-title":"Science"},{"key":"2532_CR10","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nature03441","volume":"434","author":"X Xie","year":"2005","unstructured":"Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES, Kellis M: Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature 2005, 434: 338\u201345. 10.1038\/nature03441","journal-title":"Nature"},{"key":"2532_CR11","doi-asserted-by":"publisher","first-page":"12114","DOI":"10.1073\/pnas.0402858101","volume":"101","author":"Q Zhou","year":"2004","unstructured":"Zhou Q, Wong WH: CisModule: de novo discovery of cis-regulatory modules by hierarchical mixture modeling. Proc Natl Acad Sci USA 2004, 101: 12114\u20139. 10.1073\/pnas.0402858101","journal-title":"Proc Natl Acad Sci USA"},{"key":"2532_CR12","doi-asserted-by":"publisher","first-page":"7079","DOI":"10.1073\/pnas.0408743102","volume":"102","author":"M Gupta","year":"2005","unstructured":"Gupta M, Liu JS: De novo cis-regulatory module elicitation for eukaryotic genomes. Proc Natl Acad Sci USA 2005, 102: 7079\u201384. 10.1073\/pnas.0408743102","journal-title":"Proc Natl Acad Sci USA"},{"key":"2532_CR13","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1101\/gr.4866006","volume":"16","author":"M Blanchette","year":"2006","unstructured":"Blanchette M, Bataille AR, Chen X, Poitras C, Laganiere J, Lefebvre C, Deblois G, Giguere V, Ferretti V, Bergeron D, Coulombe B, Robert F: Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression. Genome Res 2006, 16: 656\u201368. 10.1101\/gr.4866006","journal-title":"Genome Res"},{"key":"2532_CR14","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1101\/gr.4140006","volume":"16","author":"L Elnitski","year":"2006","unstructured":"Elnitski L, Jin VX, Farnham PJ, Jones SJ: Locating mammalian transcription factor binding sites: a survey of computational and experimental techniques. Genome Res 2006, 16: 1455\u201364. 10.1101\/gr.4140006","journal-title":"Genome Res"},{"key":"2532_CR15","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1038\/ng1966","volume":"39","author":"ND Heintzman","year":"2007","unstructured":"Heintzman ND, Stuart RK, Hon G, Fu Y, Ching CW, Hawkins RD, Barrera LO, Van Calcar S, Qu C, Ching KA, Wang W, Weng Z, Green RD, Crawford GE, Ren B: Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 2007, 39: 311\u2013318. 10.1038\/ng1966","journal-title":"Nat Genet"},{"key":"2532_CR16","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1126\/science.220.4598.671","volume":"220","author":"S Kirkpatrick","year":"1983","unstructured":"Kirkpatrick S, Gelatt CD Jr, Vecchi MP: Optimization by Simulated Annealing. Science 1983, 220: 617\u2013680. 10.1126\/science.220.4598.671","journal-title":"Science"},{"key":"2532_CR17","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1109\/5.18626","volume":"77","author":"LR Rabiner","year":"1989","unstructured":"Rabiner LR: A Tutorial on Hidden Markov-Models and Selected Applications in Speech Recognition. Proceedings of the IEEE 1989, 77: 257\u2013286. 10.1109\/5.18626","journal-title":"Proceedings of the IEEE"},{"key":"2532_CR18","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511790492","volume-title":"Biological Sequence Analysis","author":"R Durbin","year":"1998","unstructured":"Durbin R, Eddy S, Krogh A, Mitchison G: Biological Sequence Analysis. Cambridge University Press, Cambridge; 1998."},{"issue":"6","key":"2532_CR19","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1101\/gr.229102. Article published online before print in May 2002","volume":"12","author":"WJ Kent","year":"2002","unstructured":"Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D: The human genome browser at UCSC. Genome Res 2002, 12(6):996\u20131006.","journal-title":"Genome Res"},{"key":"2532_CR20","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/ng1789","volume":"38","author":"P Carninci","year":"2006","unstructured":"Carninci P, Sandelin A, Lenhard B, Katayama S, Shimokawa K, Ponjavic J, Semple CA, Taylor MS, Engstrom PG, Frith MC, Forrest AR, Alkema WB, Tan SL, Plessy C, Kodzius R, Ravasi T, Kasukawa T, Fukuda S, Kanamori-Katayama M, Kitazume Y, Kawaji H, Kai C, Nakamura M, Konno H, Nakano K, Mottagui-Tabar S, Arner P, Chesi A, Gustincich S, Persichetti F, Suzuki H, Grimmond SM, Wells CA, Orlando V, Wahlestedt C, Liu ET, Harbers M, Kawai J, Bajic VB, Hume DA, Hayashizaki Y: Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 2006, 38: 626\u201335. 10.1038\/ng1789","journal-title":"Nat Genet"},{"key":"2532_CR21","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/nature03877","volume":"436","author":"TH Kim","year":"2005","unstructured":"Kim TH, Barrera LO, Zheng M, Qu C, Singer MA, Richmond TA, Wu Y, Green RD, Ren B: A high-resolution map of active promoters in the human genome. Nature 2005, 436: 876\u201380. 10.1038\/nature03877","journal-title":"Nature"},{"key":"2532_CR22","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1016\/S1097-2765(02)00786-4","volume":"10","author":"P Hatzis","year":"2002","unstructured":"Hatzis P, Talianidis I: Dynamics of enhancer-promoter communication during differentiation-induced gene activation. Mol Cell 2002, 10: 1467\u201377. 10.1016\/S1097-2765(02)00786-4","journal-title":"Mol Cell"},{"key":"2532_CR23","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.molcel.2005.07.018","volume":"19","author":"Q Wang","year":"2005","unstructured":"Wang Q, Carroll JS, Brown M: Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 2005, 19: 631\u201342. 10.1016\/j.molcel.2005.07.018","journal-title":"Mol Cell"},{"key":"2532_CR24","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/S0092-8674(00)80073-2","volume":"86","author":"G Felsenfeld","year":"1996","unstructured":"Felsenfeld G: Chromatin unfolds. Cell 1996, 86: 13\u20139. 10.1016\/S0092-8674(00)80073-2","journal-title":"Cell"},{"key":"2532_CR25","volume-title":"Differential roles of promoters, enhancers, and insulators in cell-type specific gene expression","author":"G Hon","year":"2007","unstructured":"Hon G, Hawkins D, Harp LF, Ye Z, Ching KA, Antosiewicz JE, Stewart R, Thomson JA, Ren B: Differential roles of promoters, enhancers, and insulators in cell-type specific gene expression. 2007, in press."},{"key":"2532_CR26","volume-title":"ChromaGibbs: A Gibbs sampling approach to finding common chromatin modification patterns","author":"G Hon","year":"2007","unstructured":"Hon G, Ren B, Wang W: ChromaGibbs: A Gibbs sampling approach to finding common chromatin modification patterns. 2007, in press."}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-9-547.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T03:37:06Z","timestamp":1630467426000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-9-547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2008,12]]}},"alternative-id":["2532"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-9-547","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,12]]},"assertion":[{"value":"23 August 2008","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2008","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2008","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"547"}}