Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming

TY - JOUR

T1 - Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming

AU - Jeffries, Aaron Richard

AU - Uwanogho, Dafe

AU - Cocks, Graham

AU - Perfect, Leo William

AU - Dempster, Emma

AU - Mill, Jonathan

AU - Price, Jack

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - Allelic expression

KW - DNA methylation

KW - IPSC

KW - Monoallelic

KW - RNA

KW - Stem cells

UR - http://www.scopus.com/inward/record.url?scp=84989892128&partnerID=8YFLogxK

U2 - 10.1261/rna.058347.116

DO - 10.1261/rna.058347.116

M3 - Article

AN - SCOPUS:84989892128

SN - 1355-8382

VL - 22

SP - 1620

EP - 1630

JO - Rna

JF - Rna

IS - 10

ER -