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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    • "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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    • "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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