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PRC2 functions in development and congenital disorders.

ABSTRACT: 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.

SUBMITTER: Deevy O

PROVIDER: S-EPMC6803372 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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PRC2 functions in development and congenital disorders.

Deevy Orla O Bracken Adrian P AP

Development (Cambridge, England) 20191001 19

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 regu ...[more]

PMID: 31575610

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Project description:The application of genome sequencing in patients with intellectual disability and congenital anomalies (ID/CA) typically identifies causative mutations only in a minority of cases. We hypothesized that some cases of ID/CA are caused by epigenetic aberrations that dysregulate normal genome function, and that these would be missed by conventional sequencing approaches. We performed Illumina 450k DNA methylation profiling in ~500 individuals with ID/CA, who were negative for causative mutations by microarray, exome- and/or whole genome sequencing. We screened patient methylation profiles for epimutations absent in ~1,500 controls, and validated these by bisulfite sequencing, revealing that epimutations represent large methylation changes specifically on one allele. Parental studies show that approximately half represent de novo events, a rate significantly higher than that seen in controls. We identified seven recurrent events, two of which (FMR1, MEG3) have known disease associations, validating our method for detecting pathogenic epimutations. From large-scale sequencing, population and expression studies we conclude that epimutations are: (i) Frequently associated with extreme outlier and mono-allelic gene expression, with an impact comparable to loss-of-function mutations; (ii) Generally conserved across multiple tissues within an individual, validating the use of blood DNA to study ID/CA; (iii) Can occur secondary to cis-linked regulatory mutations, providing a rationale for interpreting non-coding genetic variants; (iv) Occur sporadically with a remarkably high de novo rate, and (v) Exhibit non-Mendelian inheritance, likely being reset between generations by epigenetic reprogramming during embryogenesis. We conclude that epimutations underlie 5-10% of patients with ID/CA who are refractory to conventional mutation screening, and propose that epigenome profiling represents a promising method for the study of human disease that complements sequence-based approaches.

Dataset Information

PRC2 functions in development and congenital disorders.

Publications

PRC2 functions in development and congenital disorders.

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