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

Ido Sagi, Joao C. De Pinho, Michael V. Zuccaro, Chen Atzmon, Tamar Golan-Lev, Ofra Yanuka, Robert Prosser, Alexandra Sadowy, Gloria Perez, Thiago Cabral, Benjamin Glaser, Stephen H. Tsang, Robin Goland, Mark V. Sauer, Rogerio Lobo, Nissim Benvenisty*, Dieter Egli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)419-432.e9
JournalCell Stem Cell
Volume25
Issue number3
DOIs
StatePublished - 5 Sep 2019

Bibliographical note

Funding Information:
We thank all members of the Egli and Benvenisty laboratories for valuable input. We thank D. Vershkov for advice in histological analysis, and U. Weissbein, Y. Avior, and S. Bar for help in allele-specific analysis using WGS and RNA-seq data. I.S. is supported by the Adams Fellowships Program for Doctoral Students; N.B. is the Herbert Cohn Chair in Cancer Research. This work was partially supported by the US-Israel Binational Science Foundation (grant no. 2015089 ), by the Israel Science Foundation (grant no. 494/17 ), by the Azrieli Foundation (to N.B.); by the NYSCF-Robertson Stem Cell Investigator award; and by the NYSTEM award # C32564GG (to D.E.).

Funding Information:
We thank all members of the Egli and Benvenisty laboratories for valuable input. We thank D. Vershkov for advice in histological analysis, and U. Weissbein, Y. Avior, and S. Bar for help in allele-specific analysis using WGS and RNA-seq data. I.S. is supported by the Adams Fellowships Program for Doctoral Students; N.B. is the Herbert Cohn Chair in Cancer Research. This work was partially supported by the US-Israel Binational Science Foundation (grant no. 2015089), by the Israel Science Foundation (grant no. 494/17), by the Azrieli Foundation (to N.B.); by the NYSCF-Robertson Stem Cell Investigator award; and by the NYSTEM award #C32564GG (to D.E.). I.S. J.C.D.P. N.B. and D.E. conceived the study and wrote the manuscript with input from all authors. I.S. characterized human aESC lines, generated IGF2-knockout cells, performed differentiation experiments, and analyzed the data. J.C.D.P. recruited gamete donors and performed sperm preparation. M.V.Z. assisted with the derivation of human aESC lines and generation of STR profiles. C.A. assisted with histological analysis. T.G.-L. performed karyotype analysis. O.Y. assisted with cell culture. R.P. A.S. and D.E. performed ICSI and oocyte enucleation. G.P. prepared samples for DNA methylation analysis. T.C. B.G. S.H.T. and R.G. recruited gamete donors. M.V.S. and R.L. performed oocyte donor recruitment and oocyte aspirations. D.E. derived human ESC lines. N.B. and D.E. supervised the study. N.B. is CSO of NewStem Ltd.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • IGF2
  • androgenesis
  • differentiation bias
  • genomic imprinting
  • human embryonic stem cells
  • human pluripotent stem cells
  • parental imprinting
  • parthenogenesis

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