A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Gao, Christine W.; Lin, WanYing; Riddle, Ryan C.; Kushwaha, Priyanka; Boukas, Leandros; Björnsson, Hans T.; Hansen, Kasper D.; Fahrner, Jill A.

doi:10.1172/jci.insight.173392

Cited by 4 publications

(7 citation statements)

References 85 publications

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“…The lack of early truncating mutations in more N-terminal exons of EZH2 suggests haploinsufficiency is unlikely to be the major mutational mechanism of WS. Regardless, WS-associated EZH2 variants are presumed lossof-function hypomorphs due to the reduced HMT activity demonstrated for 10 WS-associated EZH2 variants studied to date (Cohen et al 2016;Imagawa et al 2017;Lee et al 2018;Lui et al 2018;Jani et al 2019;Gao et al 2024). Taking these pieces of genetic and functional evidence together, we speculate that WS-associated EZH2 variants are indeed partial loss of function but with potential dominant negative effects.…”

Section: Introductionmentioning

confidence: 85%

“…Our discovery of dominant-negative effects by WS-associated EZH2 variants may help answer the question posed by Lui et al (2018): if the causative mutations are indeed loss-of-function, why have no early truncating mutations of EZH2 been reported in WS? One possibility proposed by Gao et al (2024) is that manifestation of the Weaver phenotype may require biallelic EZH2 protein expression, irrespective of catalytic activity. Our data agree that normal EZH2 protein levels may be necessary but suggest that perturbed catalytic activity is central to the phenotype.…”

Section: A Dominant Negative Mutational Mechanism May Explain the Lac...mentioning

confidence: 99%

“…This prediction is consistent with the known mutational spectrum and inheritance pattern of WS. Previously published models of WS suggest that the associated EZH2 variants are partial loss-of-function, but they did not include a matched comparison against the EZH2 heterozygous condition to allow testing for dominant interference (Cohen et al 2016;Lui et al 2018;Jani et al 2019;Choufani et al 2020;Gao et al 2024). We experimentally addressed this question by creating an Ezh2 heterozygous knockout mESC line in which we exogenously expressed human WS-associated EZH2 variants (Fig.…”

Section: Weaver Syndrome-associated Ezh2 Variants Can Dominant-negati...mentioning

confidence: 99%

“…Taking these pieces of genetic and functional evidence together, we speculate that WS-associated EZH2 variants are indeed partial loss of function but with potential dominant negative effects. Thus far, functional molecular studies of these Weaver WSassociated EZH2 variants have employed in vitro HMT assays, DNA methylation profiling, or assays of global H3K27 methylation (Cohen et al 2016;Lui et al 2018;Jani et al 2019;Choufani et al 2020;Gao et al 2024). However, these in vitro assays and global assessments of H3K27 methylation levels do not capture the complexity of the Polycomb system.…”

Section: Introductionmentioning

confidence: 99%

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Dominant negative effects on H3K27 methylation by Weaver syndrome-associated EZH2 variants

Deevy,

Monger,

Matrà

et al. 2023

Preprint

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Weaver syndrome (WS) is a developmental overgrowth and intellectual disability disorder caused by heterozygous mutations in EZH2. EZH2 encodes the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2) which mediates methylation of histone H3 lysine residue 27 (H3K27). Although PRC2 has been extensively studied at the molecular level, the effects of WS-associated EZH2 mutations on cells remain poorly understood. In this study, we expressed WS-associated EZH2 variants in mouse embryonic stem cells and found that they have dominant negative effects on Polycomb repressive function. These EZH2 variants decrease H3K27me2/3 and increase H3K27ac levels at intergenic regions, causing global chromatin decompaction and transcriptional upregulation of sensitive Polycomb target genes. Interestingly, a contrasting EZH2 variant linked to growth restriction caused opposing changes in H3K27 methylation and acetylation, and repressed the same cohort of Polycomb target genes. Our study provides insights into the molecular mechanisms of EZH2-mutant human growth disorders, revealing the opposing changes in chromatin and transcription associated with Weaver syndrome and growth restriction, respectively.

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Section: Introductionmentioning

confidence: 85%

Section: A Dominant Negative Mutational Mechanism May Explain the Lac...mentioning

confidence: 99%

Section: Weaver Syndrome-associated Ezh2 Variants Can Dominant-negati...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dominant negative effects on H3K27 methylation by Weaver syndrome-associated EZH2 variants

Deevy,

Monger,

Matrà

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Mice carrying the EZH2 R684C mutant, an experimental Weaver syndrome characterized by bone overgrowth, develop a relatively thick cortical bone, increased bone mineral acquisition, and mineralized extracellular matrix production of bone marrow stromal cells. The KDM6A/B inhibitor GSK-J4 counteracts bone overdevelopment in these genetically modified animals [108]. The deletion of KDM6A in cranial cells represses suture development and osteoblastic activity, including Runx2 and alkaline phosphatase expression of calvaria osteoblasts in female mice.…”

Section: Kdm6a and Kdm6bmentioning

confidence: 99%

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

Lian,

Wu,

Lin

et al. 2024

Antioxidants

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Imbalanced osteogenic cell-mediated bone gain and osteoclastic remodeling accelerates the development of osteoporosis, which is the leading risk factor of disability in the elderly. Harmonizing the metabolic actions of bone-making cells and bone resorbing cells to the mineralized matrix network is required to maintain bone mass homeostasis. The tricarboxylic acid (TCA) cycle in mitochondria is a crucial process for cellular energy production and redox homeostasis. The canonical actions of TCA cycle enzymes and intermediates are indispensable in oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis for osteogenic differentiation and osteoclast formation. Knockout mouse models identify these enzymes’ roles in bone mass and microarchitecture. In the noncanonical processes, the metabolites as a co-factor or a substrate involve epigenetic modification, including histone acetyltransferases, DNA demethylases, RNA m6A demethylases, and histone demethylases, which affect genomic stability or chromatin accessibility for cell metabolism and bone formation and resorption. The genetic manipulation of these epigenetic regulators or TCA cycle intermediate supplementation compromises age, estrogen deficiency, or inflammation-induced bone mass loss and microstructure deterioration. This review sheds light on the metabolic functions of the TCA cycle in terms of bone integrity and highlights the crosstalk of the TCA cycle and redox and epigenetic pathways in skeletal tissue metabolism and the intermediates as treatment options for delaying osteoporosis.

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Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1

Gao,

Lin,

Riddle

et al. 2023

Preprint

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Growth retardation is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth retardation in a mouse model of KS1 and further established that aKmt2d-/-chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth retardation in a mouse model of KS2,Kdm6atm1d/+. We show thatKdm6atm1d/+mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure.Kdm6atm1d/+growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a-/- chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found thatKdm6a-/-cells undergo premature, enhanced differentiation towards chondrocytes compared toKdm6a+/+controls. RNA-seq showed thatKdm6a-/-cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously onKmt2d-/-,Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression betweenKmt2d-/-andKdm6a-/-at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.

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A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Cited by 4 publications

References 85 publications

Dominant negative effects on H3K27 methylation by Weaver syndrome-associated EZH2 variants

Dominant negative effects on H3K27 methylation by Weaver syndrome-associated EZH2 variants

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease

Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1

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