Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming

Aaron Richard Jeffries*, Dafe Uwanogho, Graham Cocks, Leo William Perfect, Emma Dempster, Jonathan Mill, Jack Price

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
155 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1620-1630
Number of pages11
JournalRna
Volume22
Issue number10
Early online date18 Aug 2016
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • Allelic expression
  • DNA methylation
  • IPSC
  • Monoallelic
  • RNA
  • Stem cells

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