title: Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming.
abstract: Clonal level random allelic expression imbalance and random monoallelic expression provides cellular heterogeneity within tissues by modulating allelic dosage. Although such expression patterns have been observed in multiple cell types, little is known about when in development these stochastic allelic choices are made. We examine allelic expression patterns in human neural progenitor cells before and after epigenetic reprogramming to induced pluripotency, observing that loci previously characterized by random allelic expression imbalance (0.63% of expressed genes) are generally reset to a biallelic state in induced pluripotent stem cells (iPSCs). We subsequently neuralized the iPSCs and profiled isolated clonal neural stem cells, observing that significant random allelic expression imbalance is reestablished at 0.65% of expressed genes, including novel loci not found to show allelic expression imbalance in the original parental neural progenitor cells. Allelic expression imbalance was associated with altered DNA methylation across promoter regulatory regions, with clones characterized by skewed allelic expression being hypermethylated compared to their biallelic sister clones. Our results suggest that random allelic expression imbalance is established during lineage commitment and is associated with increased DNA methylation at the gene promoter.
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Aaron Richard
authors.initials: AR
authors.lastname: Jeffries
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Dafe Aghogho
authors.initials: DA
authors.lastname: Uwanogho
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Cocks
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Leo William
authors.initials: LW
authors.lastname: Perfect
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Dempster
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Jack
authors.initials: J
authors.lastname: Price
mesh_terms: D022981:Allelic Imbalance; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism
keywords: DNA methylation; RNA; allelic expression; iPSC; monoallelic; stem cells