Distinct Imprinting Signatures and Biased Differentiation of Human Androgenetic and Parthenogenetic Embryonic Stem Cells

Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a similar bias toward liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease. [Display omitted] •Generation of human androgenetic and parthenogenetic ESCs (aESCs and pESCs)•Comparing aESCs and pESCs identifies known and formerly undescribed imprinted genes•The uniparental cells show tissue-specific parent-of-origin differentiation biases•The imprinted gene IGF2 is involved in hepatic differentiation bias of human aESCs Benvenisty, Egli, and colleagues combine newly derived human androgenetic ESCs with parthenogenetic and bi-parental ESCs to explore parental imprinting in humans, charting the regulatory landscape of known imprinted loci, identifying previously undescribed imprinted genes, and interrogating the nature and mechanisms underlying parental-origin-driven tissue-specific differentiation biases with implications for human development and disease.