Stochastic Choice of Allelic Expression in Human Neural Stem Cells§

Authors

  • Aaron R. Jeffries,

    Corresponding author
    1. King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, Department of Neuroscience
    • King's College London, Institute of Psychiatry, Department of Neuroscience, CCBB, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, U.K.
    Search for more papers by this author
    • Telephone: +44(0)20-7848-0412; Fax: +44(0)20-7848-0986

  • Leo W. Perfect,

    1. King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, Department of Neuroscience
    Search for more papers by this author
  • Julia Ledderose,

    1. King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, Department of Neuroscience
    Search for more papers by this author
  • Leonard C. Schalkwyk,

    1. King's College London, Institute of Psychiatry, MRC SGDP Research Centre, London, United Kingdom
    Search for more papers by this author
  • Nicholas J. Bray,

    1. King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, Department of Neuroscience
    Search for more papers by this author
  • Jonathan Mill,

    1. King's College London, Institute of Psychiatry, MRC SGDP Research Centre, London, United Kingdom
    Search for more papers by this author
  • Jack Price

    1. King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, Department of Neuroscience
    Search for more papers by this author

  • Author contributions: A.R.J.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; L.W.P.: provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; J.L.: provision of study material or patients and final approval of manuscript; L.C.S.: data analysis and interpretation and final approval of manuscript; N.J.B.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript; J.M.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; J.P.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS June 19, 2012; available online without subscription through the open access option.

Abstract

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. Stem Cells2012;30:1938–1947

Ancillary