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Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

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

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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
Dates:
DateEvent
July 2019Published
3 June 2019Published Online
24 May 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
SG/16-17/02Newlife Foundation for Disabled Childrenhttp://dx.doi.org/10.13039/501100000871
G1001931Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1002279Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/M008924/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/K013807/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
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

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