{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:05:14Z","timestamp":1792501514691,"version":"4.5.0"},"reference-count":8,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HHSN275201200007C HHSN275201300026I"],"award-info":[{"award-number":["HHSN275201200007C HHSN275201300026I"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006370","name":"Small Business Innovation Research","doi-asserted-by":"publisher","award":["2034014"],"award-info":[{"award-number":["2034014"]}],"id":[{"id":"10.13039\/100006370","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>\n                    Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comprehensive network of epigenetic profiles in complex diseases, we used publicly available DNA methylation data from over 2,400 samples representing 20 cell types and various diseases. This tool, rather than detecting differentially methylated regions at specific genes, measures the intra-individual methylation variability within gene promoters to identify global shifts away from healthy regulatory states. To assess this new approach, we explored three distinct questions: 1) Are profiles of epigenetic variability tissue-specific? 2) Do diseased tissues exhibit altered epigenetic variability compared to normal tissue? 3) Can epigenetic variability be detected in complex disease? Unsupervised clustering established that global epigenetic variability in promoter regions is tissue-specific and promoter regions that are the most epigenetically stable in a specific tissue are associated with genes known to be essential for its function. Furthermore, analysis of epigenetic variability in these most stable regions distinguishes between diseased and normal tissue in multiple complex diseases. Finally, we demonstrate the clinical utility of this new tool in the assessment of a multifactorial condition, male infertility. We show that epigenetic variability in purified sperm is correlated with live birth outcomes in couples undergoing intrauterine insemination (IUI), a common fertility procedure. Men with the least epigenetically variable promoters were almost twice as likely to father a child than men with the greatest number of epigenetically variable promoters. Interestingly, no such difference was identified in men undergoing\n                    <jats:italic>in vitro<\/jats:italic>\n                    fertilization (IVF), another common fertility procedure, suggesting this as a treatment to overcome higher levels of epigenetic variability when trying to conceive.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2023.1125967","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T03:10:43Z","timestamp":1689736243000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Tissue-specific DNA methylation variability and its potential clinical value"],"prefix":"10.3389","volume":"14","author":[{"given":"Ryan H.","family":"Miller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad A.","family":"Pollard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin R.","family":"Brogaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Olson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan C.","family":"Barney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry I.","family":"Lipshultz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica B.","family":"Johnstone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yetunde O.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Hotaling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique F.","family":"Schisterman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunni L.","family":"Mumford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth I.","family":"Aston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim G.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: A flexible and comprehensive bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1016\/j.fertnstert.2015.08.019","article-title":"Aberrant sperm DNA methylation predicts male fertility status and embryo quality","volume":"104","author":"Aston","year":"2015","journal-title":"Fertil. Steril."},{"key":"B3","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1186\/gb-2007-8-9-227","article-title":"The protamine family of sperm nuclear proteins","volume":"8","author":"Balhorn","year":"2007","journal-title":"Genome Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"6796","DOI":"10.1073\/pnas.1415301111","article-title":"Notes on the role of dynamic DNA methylation in mammalian development","volume":"112","author":"Bestor","year":"2014","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1126\/science.1084564","article-title":"The human Genome Project: Lessons from large-scale biology","volume":"300","author":"Collins","year":"2003","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1186\/1471-2105-11-587","article-title":"Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis","volume":"11","author":"Du","year":"2010","journal-title":"BMC Bioinforma."},{"key":"B7","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the Xena platform","volume":"38","author":"Goldman","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.fertnstert.2021.09.009","article-title":"The impact of zinc and folic acid supplementation on sperm DNA methylation: Results from the folic acid and zinc supplementation randomized clinical trial (FAZST)","volume":"117","author":"Jenkins","year":"2021","journal-title":"Fertil. Steril."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1125967\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T03:10:47Z","timestamp":1689736247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1125967\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,19]]},"references-count":8,"alternative-id":["10.3389\/fgene.2023.1125967"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1125967","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.02.04.479170","asserted-by":"object"}]},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,19]]},"article-number":"1125967"}}