Stochastic Choice of Allelic Expression in Human Neural Stem Cells

King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, Department of Neuroscience, London, United Kingdom.
Stem Cells (Impact Factor: 6.52). 09/2012; 30(9):1938-47. DOI: 10.1002/stem.1155
Source: PubMed


Monoallelic gene expression, such as genomic imprinting, is well described. Less well-characterized are genes undergoing stochastic monoallelic expression (MA), where specific clones of cells express just one allele at a given locus. We performed genome-wide allelic expression assessment of human clonal neural stem cells derived from cerebral cortex, striatum, and spinal cord, each with differing genotypes. We assayed three separate clonal lines from each donor, distinguishing stochastic MA from genotypic effects. Roughly 2% of genes showed evidence for autosomal MA, and in about half of these, allelic expression was stochastic between different clones. Many of these loci were known neurodevelopmental genes, such as OTX2 and OLIG2. Monoallelic genes also showed increased levels of DNA methylation compared to hypomethylated biallelic loci. Identified monoallelic gene loci showed altered chromatin signatures in fetal brain, suggesting an in vivo correlate of this phenomenon. We conclude that stochastic allelic expression is prevalent in neural stem cells, providing clonal diversity to developing tissues such as the human brain.

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Available from: Aaron Richard Jeffries, Sep 16, 2014
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    • "Also, it was observed that exposure to different forms of early life traumas led to similar methylation changes in blood and brain cells (Klengel et al., 2013). It has been proposed that epigenetic changes induced early in development in particular may be present across many different tissues, because they are propagated through cell division (Feinberg & Irizarry, 2010; Jeffries et al., 2012; Mill & Heijmans, 2013). "
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    ABSTRACT: Tic disorders are moderately heritable common psychiatric disorders that can be highly troubling, both in childhood and in adulthood. In this study, we report results obtained in the first epigenome-wide association study (EWAS) of tic disorders. The subjects are participants in surveys at the Netherlands Twin Register (NTR) and the NTR biobank project. Tic disorders were measured with a self-report version of the Yale Global Tic Severity Scale Abbreviated version (YGTSS-ABBR), included in the 8th wave NTR data collection (2008). DNA methylation data consisted of 411,169 autosomal methylation sites assessed by the Illumina Infinium HumanMethylation450 BeadChip Kit (HM450k array). Phenotype and DNA methylation data were available in 1,678 subjects (mean age = 41.5). No probes reached genome-wide significance (p < 1.2 × 10-7). The strongest associated probe was cg15583738, located in an intergenic region on chromosome 8 (p = 1.98 × 10-6). Several of the top ranking probes (p < 1 × 10-4) were in or nearby genes previously associated with neurological disorders (e.g., GABBRI, BLM, and ADAM10), warranting their further investigation in relation to tic disorders. The top significantly enriched gene ontology (GO) terms among higher ranking methylation sites included anatomical structure morphogenesis (GO:0009653, p = 4.6 × 10-15) developmental process (GO:0032502, p = 2.96 × 10-12), and cellular developmental process (GO:0048869, p = 1.96 × 10-12). Overall, these results provide a first insight into the epigenetic mechanisms of tic disorders. This first study assesses the role of DNA methylation in tic disorders, and it lays the foundations for future work aiming to unravel the biological mechanisms underlying the architecture of this disorder.
    Twin Research and Human Genetics 10/2015; DOI:10.1017/thg.2015.72 · 2.30 Impact Factor
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    • "This epigenetic driven allelic expression choice contributes to clonal diversity and functional heterozygosity at the cellular level [7], and we have hypothesized that it might, for example, contribute to discordance between monozygotic twins [5]. While the exact impact stochastic monoallelic expression has on development is unclear, our study of allelic expression in human neural stem cells identified a number of neurodevelopmental genes showing this form of allelic expression control [5]. We therefore asked whether stochastic monoallelic expressed genes have any potential significance as a risk factor in the neurodevelopmental disorders, autism and schizophrenia. "
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    ABSTRACT: Random or stochastic monoallelic expressed genes (StMA genes) represent a unique form of monoallelic expression where allelic choice is made at random early in development. The consequential clonal diversity provides opportunity for functional heterozygosity in tissues such as the brain, and can impact on both development and disease. We investigate the relationship of StMA expressed genes previously identified in clonal neural stem cells with the neurodevelopmental disorders autism and schizophrenia. We found that StMA genes show an overrepresentation of schizophrenia risk candidates identified by genome wide association studies from the genetic association database. Similar suggestive enrichment was also found for genes from the NHGRI genome-wide association study catalog and a psychiatric genetics consortium schizophrenia dataset although these latter more robust gene lists did not achieve statistical significance. We also examined multiple sources of copy number variation (CNV) datasets from autism and schizophrenia cohorts. After taking into account total gene numbers and CNV size, both autism and schizophrenia associated CNVs appeared to show an enrichment of StMA genes relative to the control CNV datasets. Since the StMA genes were originally identified in neural stem cells, bias due to the neural transcriptome is possible. To address this, we randomly sampled neural stem cell expressed genes and repeated the tests. After a significant number of iterations, neural stem cell expressed genes did not show an overrepresentation in autism or schizophrenia CNV datasets. Therefore, irrespective of the neural derived transcriptome, StMA genes originally identified in neural stem cells show an overrepresentation in CNVs associated with autism and schizophrenia. If this association is functional, then the regulation (or dysregulation) of this form of allelic expression status within tissues such as the brain may be a contributory risk factor for neurodevelopmental disorders and may also influence disease discordance sometimes observed in monozygotic twins.
    PLoS ONE 12/2013; 8(12):e85093. DOI:10.1371/journal.pone.0085093 · 3.23 Impact Factor
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    • "The term " epigenetic modifications " reflects mitotically heritable changes in gene expression patterns that are not encoded in the primary DNA sequence. A variety of environmental influences, and rare-stochastic monoallelic expression toward a specific cellular outcome (Jeffries et al., 2012), have been shown to harbor long-lasting effects across the life span of an organism through epigenetic modifications including DNA (hydroxy) methylation, histone methylation, and acetylation, and regulation by noncoding RNAs (ncRNAs), with different modifications resulting in a different phenotype. Accordingly, as also reviewed by Sato et al. (2011), epigenetic mechanisms may affect the expression of miRNAs in both physiological and pathologic conditions in a tissue-specific manner. "
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    ABSTRACT: Alzheimer's disease (AD) is a complex neurodegenerative disorder involving dysregulation of many biological pathways at multiple levels. Classical epigenetic mechanisms, including DNA methylation and histone modifications, and regulation by microRNAs (miRNAs), are among the major regulatory elements that control these pathways at the molecular level, with epigenetic modifications regulating gene expression transcriptionally and miRNAs suppressing gene expression posttranscriptionally. Epigenetic mechanisms and miRNAs have recently been shown to closely interact with each other, thereby creating reciprocal regulatory circuits, which appear to be disrupted in neuronal and glial cells affected by AD. Here, we review those miRNAs implicated in AD that are regulated by promoter DNA methylation and/or chromatin modifications and, which frequently direct the expression of constituents of the epigenetic machinery, concluding with the delineation of a complex epigenetic-miRNA regulatory network and its alterations in AD.
    Neurobiology of aging 10/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.10.082 · 5.01 Impact Factor
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