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dc.contributor.authorLim, Andrew S. P.en_US
dc.contributor.authorSrivastava, Gyan P.en_US
dc.contributor.authorYu, Leien_US
dc.contributor.authorChibnik, Lori B.en_US
dc.contributor.authorXu, Jishuen_US
dc.contributor.authorBuchman, Aron S.en_US
dc.contributor.authorSchneider, Julie A.en_US
dc.contributor.authorMyers, Amanda J.en_US
dc.contributor.authorBennett, David A.en_US
dc.contributor.authorDe Jager, Philip L.en_US
dc.date.accessioned2014-12-02T21:27:18Z
dc.date.issued2014en_US
dc.identifier.citationLim, Andrew S. P., Gyan P. Srivastava, Lei Yu, Lori B. Chibnik, Jishu Xu, Aron S. Buchman, Julie A. Schneider, Amanda J. Myers, David A. Bennett, and Philip L. De Jager. 2014. “24-Hour Rhythms of DNA Methylation and Their Relation with Rhythms of RNA Expression in the Human Dorsolateral Prefrontal Cortex.” PLoS Genetics 10 (11): e1004792. doi:10.1371/journal.pgen.1004792. http://dx.doi.org/10.1371/journal.pgen.1004792.en
dc.identifier.issn1553-7390en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13454635
dc.description.abstractCircadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1–3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pgen.1004792en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222754/pdf/en
dash.licenseLAAen_US
dc.subjectBiology and life sciencesen
dc.subjectAnatomyen
dc.subjectBrainen
dc.subjectCerebral Cortexen
dc.subjectEntorhinal Cortexen
dc.subjectNeocortexen
dc.subjectBiochemistryen
dc.subjectDNAen
dc.subjectDNA modificationen
dc.subjectDNA methylationen
dc.subjectCircadian Oscillatorsen
dc.subjectChronobiologyen
dc.subjectCircadian Rhythmsen
dc.subjectComputational Biologyen
dc.subjectGenome Analysisen
dc.subjectTranscriptome Analysisen
dc.subjectSerial Analysis of Gene Expressionen
dc.subjectGeneticsen
dc.subjectGene Expressionen
dc.subjectGenomicsen
dc.subjectMedicine and Health Sciencesen
dc.subjectPhysical Sciencesen
dc.subjectMathematicsen
dc.subjectDiscrete Mathematicsen
dc.subjectCombinatoricsen
dc.subjectPermutationen
dc.subjectStatistics (Mathematics)en
dc.subjectStatistical Methodsen
dc.subjectTime Series Analysisen
dc.subjectMathematical and Statistical Techniquesen
dc.title24-Hour Rhythms of DNA Methylation and Their Relation with Rhythms of RNA Expression in the Human Dorsolateral Prefrontal Cortexen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS Geneticsen
dash.depositing.authorSrivastava, Gyan P.en_US
dc.date.available2014-12-02T21:27:18Z
dc.identifier.doi10.1371/journal.pgen.1004792*
dash.contributor.affiliatedSrivastava, Gyan
dash.contributor.affiliatedChibnik, Lori
dash.contributor.affiliatedDe Jager, Philip


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