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

Shiran Bar, Dan Vershkov, Gal Keshet, Elyad Lezmi, Naama Meller, Atilgan Yilmaz, Ofra Yanuka, Malka Nissim-Rafinia, Eran Meshorer, Talia Eldar-Geva and Nissim Benvenisty ()
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Shiran Bar: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Dan Vershkov: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Gal Keshet: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Elyad Lezmi: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Naama Meller: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Atilgan Yilmaz: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Ofra Yanuka: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Malka Nissim-Rafinia: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Eran Meshorer: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram
Talia Eldar-Geva: IVF Unit, Division of Obstetrics and Gynecology, Shaare Zedek Medical Center
Nissim Benvenisty: The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26949-7

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