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The Journal of Clinical Endocrinology... Jan 2024Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature,... (Review)
Review
Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.
Topics: Humans; Autism Spectrum Disorder; Abnormalities, Multiple; Syndrome; Histone Methyltransferases; Intellectual Disability; Epigenesis, Genetic
PubMed: 37450557
DOI: 10.1210/clinem/dgad420 -
Development (Cambridge, England) Oct 2019Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for... (Review)
Review
Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for normal development and its loss of function thus results in a range of developmental phenotypes. Here, we review the latest advances in our understanding of mammalian PRC2 activity and present an updated summary of the phenotypes associated with its loss of function in mice. We then discuss recent studies that have highlighted regulatory interplay between the modifications laid down by PRC2 and other chromatin modifiers, including NSD1 and DNMT3A. Finally, we propose a model in which the dysregulation of these modifications at intergenic regions is a shared molecular feature of genetically distinct but highly phenotypically similar overgrowth syndromes in humans.
Topics: Animals; Congenital Abnormalities; Embryonic Development; Humans; Mammals; Models, Biological; Polycomb Repressive Complex 2; Signal Transduction
PubMed: 31575610
DOI: 10.1242/dev.181354 -
Current Opinion in Structural Biology Apr 2021The polycomb repressive complex 2 (PRC2) is a conserved multiprotein, repressive chromatin complex essential for development and maintenance of eukaryotic cellular... (Review)
Review
The polycomb repressive complex 2 (PRC2) is a conserved multiprotein, repressive chromatin complex essential for development and maintenance of eukaryotic cellular identity. PRC2 comprises a trimeric core of SUZ12, EED and EZH1/2, which together with RBBP4/7 is sufficient to catalyse mono-methylation, di-methylation and tri-methylation of histone H3 at lysine 27 (H3K27me1/2/3). These histone methyltransferase activities of PRC2 are deregulated in several human cancers and certain developmental disorders, such as Weaver Syndrome. Core PRC2 associates with several accessory proteins, which organise to define two main subassemblies, PRC2.1 and PRC2.2. Here we review new biochemical and structural studies that are providing critical insights into how core and accessory PRC2 subunits coordinate the faithful deposition of H3K27 methylations genome-wide.
Topics: Chromatin; Histones; Humans; Methylation; Polycomb Repressive Complex 2; Protein Processing, Post-Translational
PubMed: 33232890
DOI: 10.1016/j.sbi.2020.10.017 -
Operative Neurosurgery (Hagerstown, Md.) Oct 2021
Commentary: Posteromedial Hypothalamic Deep Brain Stimulation for Refractory Aggressiveness in a Patient With Weaver Syndrome: Clinical, Technical Report, and Operative Video.
Topics: Abnormalities, Multiple; Congenital Hypothyroidism; Craniofacial Abnormalities; Deep Brain Stimulation; Hand Deformities, Congenital; Humans
PubMed: 34467982
DOI: 10.1093/ons/opab293 -
JCI Insight Jan 2024Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27...
Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.
Topics: Animals; Mice; Osteogenesis; Fibroblasts; Polycomb Repressive Complex 2; Disease Models, Animal; Histone Demethylases
PubMed: 38015625
DOI: 10.1172/jci.insight.173392 -
BioRxiv : the Preprint Server For... Jun 2023Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in , which encodes the predominant H3K27...
Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in , which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, p.R684C. mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. mice had abnormal bone parameters indicative of skeletal overgrowth, and osteoblasts showed increased osteogenic activity. RNA-seq comparing osteoblasts differentiated from and bone marrow mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases Kdm6a/6b substantially reversed the excessive osteogenesis in cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state, and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.
PubMed: 37425751
DOI: 10.1101/2023.06.23.546270 -
Brain Sciences Dec 2021Deep brain stimulation (DBS) requires a precise localization, which is especially difficult at the hypothalamus, because it is usually performed in anesthetized...
Deep brain stimulation (DBS) requires a precise localization, which is especially difficult at the hypothalamus, because it is usually performed in anesthetized patients. We aimed to characterize the neurophysiological properties posteromedial hypothalamus (PMH), identified by the best neurophysiological response to electrical stimulation. We obtained microelectrode recordings from four patients with intractable aggressivity operated under general anesthesia. We pooled data from 1.5 mm at PMH, 1.5 mm upper (uPMH) and 1.5 mm lower (lPMH). We analyzed 178 units, characterized by the mean action potential (mAP). Only 11% were negative. We identified the next types of units: P1N1 (30.9%), N1P1N2 (29.8%), P1P2N1 (16.3%), N1P1 and N1N2P1 (6.2%) and P1N1P2 (5.0%). Besides, atypical action potentials (amAP) were recorded in 11.8%. PMH was highly different in cell composition from uPMH and lPMH, exhibiting also a higher percentage of amAP. Different kinds of cells shared similar features for the three hypothalamic regions. Although features for discharge pattern did not show region specificity, the probability mass function of inter-spike interval were different for all the three regions. Comparison of the same kind of mAP with thalamic neurons previously published demonstrate that most of cells are different for derivatives, amplitude and/or duration of repolarization and depolarization phases and also for the first phase, demonstrating a highly specificity for both brain centers. Therefore, the different properties described for PMH can be used to positively refine targeting, even under general anesthesia. Besides, we describe by first time the presence of atypical extracellular action potentials.
PubMed: 35053786
DOI: 10.3390/brainsci12010043 -
Animal Genetics Oct 2022Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs...
Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs characterized by uncoordinated movements and spasticity, worsening progressively and leading to inability to walk. Pedigree analysis suggested an autosomal recessive transmission. By whole genome sequencing and variant filtering of an affected dog we identified a PNPLA8:c.1169_1170dupTT variant. This variant, located in PNPLA8 (Patatin Like Phospholipase Domain Containing 8), was predicted to induce a PNPLA8:p.(His391PhefsTer394) frameshift, leading to a premature stop codon in the protein. The truncated protein was predicted to lack the functional patatin catalytic domain of PNPLA8, a calcium-independent phospholipase. PNPLA8 is known to be essential for maintaining mitochondrial energy production through tailoring mitochondrial membrane lipid metabolism and composition. The Australian Shepherd ataxia shares molecular and clinical features with Weaver syndrome in cattle and the mitochondrial-related neurodegeneration associated with PNPLA8 loss-of-function variants in humans. By genotyping a cohort of 85 control Australian Shepherd dogs sampled in France, we found a 4.7% carrier frequency. The PNPLA8:c.[1169_1170dupTT] allele is easily detectable with a genetic test to avoid at-risk matings.
Topics: Animals; Australia; Cattle; Cattle Diseases; Dog Diseases; Dogs; Frameshift Mutation; Humans; Pedigree; Phospholipases; Spinocerebellar Degenerations
PubMed: 35864734
DOI: 10.1111/age.13245 -
Molecular Cell Nov 2020Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP...
Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP (CXorf67), respectively. H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3 lysine 27 trimethylation (H3K27me3) levels; however, residual peaks of H3K27me3 remain at CpG islands (CGIs) through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with PRC2 that is allosterically activated by H3K27me3 at CGIs and impede its spreading. Moreover, H3 K27M oncohistones reduce H3K27me3 in trans, independent of their incorporation into the chromatin. Although EZHIP is not found outside placental mammals, expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism. Our results provide mechanistic insights for the retention of residual H3K27me3 in tumors driven by H3 K27M and EZHIP.
Topics: Allosteric Regulation; Animals; Chromatin; CpG Islands; DNA Methylation; Drosophila melanogaster; Gene Expression Regulation, Neoplastic; Histones; Humans; Mice; Mutation; Oncogene Proteins; Polycomb Repressive Complex 2
PubMed: 33049227
DOI: 10.1016/j.molcel.2020.09.028