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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    • "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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    • "Studies of random allelic expression patterns should shed light on the roles of cellular individuality. Interestingly, stochastic allelic expression is also observed in immortalized neural clones from human fetal brain, indicating that neurons exhibit clonal diversity in the developing brain (Jeffries et al., 2012). "
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    ABSTRACT: The mammalian brain is a complex multicellular system involving enormous numbers of neurons. The neuron is the basic functional unit of the brain, and neurons are organized by specialized intercellular connections into circuits with many other neurons. Physiological studies have revealed that individual neurons have remarkably selective response properties, and this individuality is a fundamental requirement for building complex and functionally diverse neural networks. Recent molecular biological studies have revealed genetic bases for neuronal individuality in the mammalian brain. For example, in the rodent olfactory epithelium, individual olfactory neurons express only one type of odorant receptor (OR) out of the over 1000 ORs encoded in the genome. The expressed OR determines the neuron's selective chemosensory response and specifies its axonal targeting to a particular olfactory glomerulus in the olfactory bulb. Neuronal diversity can also be generated in individual cells by the independent and stochastic expression of autosomal alleles, which leads to functional heterozygosity among neurons. Among the many genes that show autosomal stochastic monoallelic expression, approximately 50 members of the clustered protocadherins (Pcdhs) are stochastically expressed in individual neurons in distinct combinations. The clustered Pcdhs belong to a large subfamily of the cadherin superfamily of homophilic cell-adhesion proteins. Loss-of-function analyses show that the clustered Pcdhs have critical functions in the accuracy of axonal projections, synaptic formation, dendritic arborization, and neuronal survival. In addition, cis-tetramers, composed of heteromultimeric clustered Pcdh members, represent selective binding units for cell-cell interactions, and provide exponential numbers of possible cell-surface relationships between individual neurons. The extensive molecular diversity of neuronal cell-surface proteins affects neurons' individual properties and connectivities. The molecular features of the diverse clustered Pcdh molecules suggest that they provide a genetic basis for neuronal individuality and appropriate neuronal wiring in the brain.
    Journal of neurogenetics 06/2013; 27(3). DOI:10.3109/01677063.2013.801969 · 1.27 Impact Factor
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