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Molecular Cell May 2018PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its...
PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifested little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2 oncogenic mutations. These results revealed critical implications for the regulation and biology of PRC2 and a vulnerability in tackling PRC2-addicted cancers.
Topics: Abnormalities, Multiple; Allosteric Regulation; Cell Line, Tumor; Chromatin; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Hand Deformities, Congenital; Histones; Humans; Neoplasms; Polycomb Repressive Complex 2
PubMed: 29681499
DOI: 10.1016/j.molcel.2018.03.020 -
Human Mutation Mar 2016Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual...
Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.
Topics: Abnormalities, Multiple; Congenital Hypothyroidism; Craniofacial Abnormalities; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Infant; Infant, Newborn; Male; Polycomb Repressive Complex 2
PubMed: 26694085
DOI: 10.1002/humu.22946 -
American Journal of Medical Genetics.... Apr 2019Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an...
Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished.
Topics: Abnormalities, Multiple; Adult; Child; Congenital Hypothyroidism; Craniofacial Abnormalities; Developmental Disabilities; Enhancer of Zeste Homolog 2 Protein; Female; Fingers; Growth Disorders; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Microcephaly; Muscle Hypotonia; Mutation; Myopia; Obesity; Phenotype; Polycomb Repressive Complex 2; Retinal Degeneration; Exome Sequencing; Young Adult
PubMed: 30793471
DOI: 10.1002/ajmg.a.61066 -
Oncotarget Nov 2018[This corrects the article DOI: 10.18632/oncotarget.385.].
[This corrects the article DOI: 10.18632/oncotarget.385.].
PubMed: 30613354
DOI: 10.18632/oncotarget.26429 -
Cold Spring Harbor Molecular Case... Aug 2018Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental...
Co-occurrence of a maternally inherited duplication and a paternally inherited pathogenic variant in in a child with growth retardation and severe short stature: atypical Weaver syndrome or evidence of a dosage effect?
Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes and , which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase () gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including ) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for , the co-occurrence of a duplication involving this gene and a pathogenic alteration in in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.
Topics: Abnormalities, Multiple; Adult; Child; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Enhancer of Zeste Homolog 2 Protein; Female; Gene Dosage; Gene Duplication; Hand Deformities, Congenital; Humans; Male; Pedigree; Phenotype
PubMed: 29802153
DOI: 10.1101/mcs.a002899 -
Nature Communications Dec 2015Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by...
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
Topics: DNA Methylation; Gene Expression Regulation; Genome, Human; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Nuclear Proteins; Sotos Syndrome
PubMed: 26690673
DOI: 10.1038/ncomms10207 -
Human Mutation Jun 2017Weaver syndrome (WS) is a rare congenital overgrowth disorder caused by heterozygous mutations in EZH2 (enhancer of zeste homolog 2) or EED (embryonic ectoderm...
Weaver syndrome (WS) is a rare congenital overgrowth disorder caused by heterozygous mutations in EZH2 (enhancer of zeste homolog 2) or EED (embryonic ectoderm development). EZH2 and EED are core components of the polycomb repressive complex 2 (PRC2), which possesses histone methyltransferase activity and catalyzes trimethylation of histone H3 at lysine 27. Here, we analyzed eight probands with clinically suspected WS by whole-exome sequencing and identified three mutations: a 25.4-kb deletion partially involving EZH2 and CUL1 (individual 1), a missense mutation (c.707G>C, p.Arg236Thr) in EED (individual 2), and a missense mutation (c.1829A>T, p.Glu610Val) in SUZ12 (suppressor of zeste 12 homolog) (individual 3) inherited from her father (individual 4) with a mosaic mutation. SUZ12 is another component of PRC2 and germline mutations in SUZ12 have not been previously reported in humans. In vitro functional analyses demonstrated that the identified EED and SUZ12 missense mutations cause decreased trimethylation of lysine 27 of histone H3. These data indicate that loss-of-function mutations of PRC2 components are an important cause of WS.
Topics: Abnormalities, Multiple; Adult; Child; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; Cullin Proteins; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Heterozygote; Histones; Humans; Male; Methylation; Mutation; Neoplasm Proteins; Pedigree; Polycomb Repressive Complex 2; Protein Interaction Maps; Transcription Factors
PubMed: 28229514
DOI: 10.1002/humu.23200 -
American Journal of Medical Genetics.... Feb 2017Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic...
Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features. Pathogenic variants in EZH2, a histone methyltransferase, have previously been identified as a cause of Weaver syndrome. However, the underlying molecular cause in many patients remains unknown. We report a patient with a clinical diagnosis of Weaver syndrome whose exome was initially non-diagnostic. Reports in the medical literature of EED associated overgrowth prompted re-analysis of the patient's original exome data. The patient was found to have a likely pathogenic variant in EED. These findings support that Weaver syndrome is a disorder with locus heterogeneity and can be due to pathogenic variants in either EZH2 or EED. This case highlights the utility of exome sequencing as a clinical diagnostic tool for novel gene discovery as well as the importance of re-examination of exome data as new information about gene-disease associations becomes available. © 2016 Wiley Periodicals, Inc.
Topics: Abnormalities, Multiple; Comparative Genomic Hybridization; Congenital Hypothyroidism; Craniofacial Abnormalities; Facies; Female; Genetic Association Studies; Hand Deformities, Congenital; Humans; Infant; Mutation; Phenotype; Physical Examination; Polycomb Repressive Complex 2; Sequence Analysis, DNA
PubMed: 27868325
DOI: 10.1002/ajmg.a.38055 -
American Journal of Human Genetics May 2020Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core...
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase 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.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Cohort Studies; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Female; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Male; Mosaicism; Mutation; Mutation, Missense; Neoplasm Proteins; Polycomb Repressive Complex 2; Reproducibility of Results; Transcription Factors; Young Adult
PubMed: 32243864
DOI: 10.1016/j.ajhg.2020.03.008 -
Journal of Human Genetics Apr 2018Overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features are the main symptoms of Weaver syndrome,... (Review)
Review
Overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features are the main symptoms of Weaver syndrome, a rare condition caused by mutations in EZH2 gene. Recently, in four patients with Weaver-like symptoms without mutations in EZH2 gene, pathogenic variants in EED were described. We present another patient clinically diagnosed with Weaver syndrome in whom WES revealed an EED de novo mutation affecting two neighboring aminoacids, NM_003797.3:c.917_919delinsCGG/p.(Arg306_Asn307delinsThrAsp) located in one allele (in cis). Our observation, together with previous reports suggests that EED gene testing is warranted in patients with the overgrowth syndrome features and suspicion of Weaver syndrome with normal results of EZH2 gene sequencing.
Topics: Abnormalities, Multiple; Alleles; Amino Acid Substitution; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Mutational Analysis; Facies; Hand Deformities, Congenital; Humans; Infant; Male; Mutation; Phenotype; Polycomb Repressive Complex 2; Exome Sequencing
PubMed: 29410511
DOI: 10.1038/s10038-017-0391-x