Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming.
Cold Spring Harbor Laboratory Press for RNA Society
© 2016 Jeffries et al. This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
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.
The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115439, the resources of which are composed of financial support from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ inkind contribution. This work was also supported in part by funding from the Mortimer D. Sackler Foundation. DNA methylation profiling was funded by Medical Research Council grant MR/K013807/ 1 to J.M.
This is the final version of the article. Available from the publisher via the DOI in this record.
Vol. 22, pp. 1620 - 1630
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