Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging
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Genome Res.-2019-Jeffries-1057 ...
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Author
Jeffries, Aaron RMaroofian, Reza
Salter, Claire G
Chioza, Barry A
Cross, Harold E
Patton, Michael A
Dempster, Emma
Temple, I Karen
Mackay, Deborah J G
Rezwan, Faisal I
Aksglaede, Lise
Baralle, Diana
Dabir, Tabib
Hunter, Matthew F
Kamath, Arveen
Kumar, Ajith
Newbury-Ecob, Ruth
Selicorni, Angelo
Springer, Amanda
Van Maldergem, Lionel
Varghese, Vinod
Yachelevich, Naomi
Tatton-Brown, Katrina
Mill, Jonathan
Crosby, Andrew H
Baple, Emma L
Affiliation
Univ Arizona, Sch Med, Dept Ophthalmol & Vis SciIssue Date
2019-07
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Jeffries, A. R., Maroofian, R., Salter, C. G., Chioza, B. A., Cross, H. E., Patton, M. A., ... & Aksglæde, L. (2019). Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. Genome research, gr-243584.Journal
GENOME RESEARCHRights
© 2019 Jeffries et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.Note
Open access articleISSN
1088-9051EISSN
1549-5469PubMed ID
31160375Version
Final published versionSponsors
Newlife Foundation for Disabled Children [SG/16-17/02]; Medical Research Council (MRC) [G1001931]; MRC [MR/M008924/1, MR/K013807/1, G1002279]; Amish communityae974a485f413a2113503eed53cd6c53
10.1101/gr.243584.118
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Except where otherwise noted, this item's license is described as © 2019 Jeffries et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
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