Jeffries, AR;
Maroofian, R;
Salter, CG;
Chioza, BA;
Cross, HE;
Patton, MA;
Dempster, E;
Temple, IK;
Mackay, DJG;
Rezwan, FI;
et al.
Jeffries, AR; Maroofian, R; Salter, CG; Chioza, BA; Cross, HE; Patton, MA; Dempster, E; Temple, IK; Mackay, DJG; Rezwan, FI; Aksglaede, L; Baralle, D; Dabir, T; Hunter, MF; Kamath, A; Kumar, A; Newbury-Ecob, R; Selicorni, A; Springer, A; Van Maldergem, L; Varghese, V; Yachelevich, N; Tatton-Brown, K; Mill, J; Crosby, AH; Baple, EL
(2019)
Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.
Genome Res, 29 (7).
pp. 1057-1066.
ISSN 1549-5469
https://doi.org/10.1101/gr.243584.118
SGUL Authors: Maroofian, Reza
|
PDF
Published Version
Available under License Creative Commons Attribution. Download (995kB) | Preview |
|
|
PDF
Accepted Version
Available under License Creative Commons Attribution. Download (1MB) | Preview |
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.
Item Type: | Article | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Additional Information: | © 2019 Jeffries et al.; Published by Cold Spring Harbor Laboratory Press 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/. | ||||||||||||||||||
Keywords: | 06 Biological Sciences, 11 Medical And Health Sciences, Bioinformatics | ||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||||||||||||
Journal or Publication Title: | Genome Res | ||||||||||||||||||
ISSN: | 1549-5469 | ||||||||||||||||||
Language: | eng | ||||||||||||||||||
Publisher License: | Creative Commons: Attribution 4.0 | ||||||||||||||||||
Projects: |
|
||||||||||||||||||
PubMed ID: | 31160375 | ||||||||||||||||||
Web of Science ID: | WOS:000473730600002 | ||||||||||||||||||
Go to PubMed abstract | |||||||||||||||||||
URI: | https://openaccess.sgul.ac.uk/id/eprint/110920 | ||||||||||||||||||
Publisher's version: | https://doi.org/10.1101/gr.243584.118 |
Statistics
Actions (login required)
![]() |
Edit Item |