DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
AMERICAN JOURNAL OF HUMAN GENETICS
Authors: Choufani, Sanaa; Gibson, William T.; Turinsky, Andrei L.; Chung, Brian H. Y.; Wang, Tianren; Garg, Kopal; Vitriolo, Alessandro; Cohen, Ana S. A.; Cyrus, Sharri; Goodman, Sarah; Chater-Diehl, Eric; Brzezinski, Jack; Brudno, Michael; Ming, Luk Ho; White, Susan M.; Lynch, Sally Ann; Clericuzio, Carol; Temple, I. Karen; Flinter, Frances; McConnell, Vivienne; Cushing, Tom; Bird, Lynne M.; Splitt, Miranda; Kerr, Bronwyn; Scherer, Stephen W.; Machado, Jerry; Imagawa, Eri; Okamoto, Nobuhiko; Matsumoto, Naomichi; Testa, Guiseppe; Iascone, Maria; Tenconi, Romano; Caluseriu, Oana; Mendoza-Londono, Roberto; Chitayat, David; Cytrynbaum, Cheryl; Tatton-Brown, Katrina; Weksberg, Rosanna
Abstract
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyl-transferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
Poly(ADP-ribosylation) regulates chromatin organization through histone H3 modification and DNA rnethylation of the first cell cycle of mouse embryos
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Osada, Tomoharu; Ryden, Anna-Margareta; Masutani, Mitsuko
Abstract
We examined the roles of poly(ADP-ribosylation) in chromatin remodeling during the first cell cycle of mouse embryos. Drug-based inhibition of poly(ADP-ribosylation) by a PARP inhibitor, PJ-34, revealed up-regulation of dimethylation of histone H3 at lysine 4 in male pronuclei and down-regulation of dimethylation of histone H3 at lysine 9 (H3K9) and lysine 27 (H3K27). Association of poly(ADP-ribosylation) with histone modification was suggested to be supported by the interaction of Suz12, a histone methyltransferase in the polycomb complex, with Parp1. PARP activity was suggested to be required for a proper localization and maintenance of Suz12 on chromosomes. Notably, DNA methylation level of female pronuclei in one-cell embryos was robustly decreased by PJ-34. Electron microscopic analysis showed a frequent appearance of unusual electron-dense areas within the female pronuclei, implying the disorganized and hypercondensed chromatin ultrastructure. These results show that poly(ADP-ribosylation) is important for the integrity of non-equivalent epigenetic dynamics of pronuclei during the first cell cycle of mouse embryos. (C) 2013 Elsevier Inc. All rights reserved.
COA
Publication 
Loading ......
