4.8 Article

Identifying regulators of parental imprinting by CRISPR/Cas9 screening in haploid human embryonic stem cells

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26949-7

Keywords

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Funding

  1. Israel Science Foundation [494/17]
  2. Israel Precision Medicine Program
  3. Rosetrees Trust
  4. Azrieli Foundation

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Genetic imprinting is crucial for monoallelic gene expression in embryonic development, with differentially methylated regions playing a key role. This study used haploid parthenogenic embryonic stem cells to identify factors involved in regulating imprinted genes, highlighting the essential role of ATF7IP in repressing paternally-expressed genes.
Genetic imprinting ensures monoallelic gene expression critical for normal embryonic development. Here the authors take advantage of human haploid parthenogenic embryonic stem cells lacking paternal alleles to identify, by genome-wide screening, factors involved in the regulation of imprinted genes. In mammals, imprinted genes are regulated by differentially methylated regions (DMRs) that are inherited from germ cells, leading to monoallelic expression in accordance with parent-of-origin. Yet, it is largely unknown how imprinted DMRs are maintained in human embryos despite global DNA demethylation following fertilization. Here, we explored the mechanisms involved in imprinting regulation by employing human parthenogenetic embryonic stem cells (hpESCs), which lack paternal alleles. We show that although global loss of DNA methylation in hpESCs affects most imprinted DMRs, many paternally-expressed genes (PEGs) remain repressed. To search for factors regulating PEGs, we performed a genome-wide CRISPR/Cas9 screen in haploid hpESCs. This revealed ATF7IP as an essential repressor of a set of PEGs, which we further show is also required for silencing sperm-specific genes. Our study reinforces an important role for histone modifications in regulating imprinted genes and suggests a link between parental imprinting and germ cell identity.

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