Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines.
Investigation of the epigenetic stability of human embryonic stem cells (hESCs) is a crucial step for their use in cell-replacement therapies, as well as for assessing whether hESCs model epigenetic regulation in human pre-implantation cell types. To address these issues, we have examined the expression of imprinted genes in a previous study and more recently in 46 individual hESC lines as part of the International Stem Cell Initiative. Our results show that nearly all hESC lines examined possessed a substantial degree of epigenetic stability, despite differences in genetic background and in their derivation and initial propagation conditions. However, some hESCs did show loss of allele-specific expression, which could have implications for hESC differentiation and epigenetic stability (both in vitro and after clinical transplantation). A benefit of our and other recent studies of genomic imprinting in hESCs was the identification of imprinted genes that provide a useful indication of epigenetic stability. SNRPN, IPW and KCNQ1OT1 were highly stable and thus appeared insensitive to perturbation; in contrast, H19, IGF2 and MEG3 were more variable and thus could potentially provide a sensitive indication of epigenetic status. In this review, we examine the differences between imprinted genes in their susceptibility to perturbation and discuss the potential molecular basis for these differences. This examination provides insight into the regulation of genomic imprinting in hESCs and the corresponding peri-implantation stages of human development.
Rugg-Gunn
Peter J
PJ
Department of Surgery and Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 OXY, UK. pjrg@sickkids.ca
Ferguson-Smith
Anne C
AC
Pedersen
Roger A
RA
D002460:Cell Line; D002874:Chromosome Mapping; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D042822:Genomic Instability; D006801:Humans; D008297:Male; D039904:Pluripotent Stem Cells / Q000378:metabolism