Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Abstract

Mouse embryonic stem cells (mESCs) are a key component in generating mouse models for human diseases and performing basic research on pluripotency, but how many genes are essential for mESCs is still unknown. We performed a genome-wide screen for essential genes in mESCs and compared it to human cells. We found that essential genes are enriched for basic cellular functions, are highly expressed in mESCs, and tend to lack paralog genes. Notably, we discovered that genes that are essential specifically in mESCs play a role in pathways associated with their pluripotent state. We show that 25% of human genes that are intolerant to loss-of-function mutations are essential in mouse or human ESCs and that the human phenotypes most significantly associated with essential genes are neurodevelopmental. Our results provide insights into essential genes in the mouse, the pathways which govern pluripotency, and suggest that many genes associated with neurodevelopmental disorders are essential at very early embryonic stages.

Global translation during early development depends on the essential transcription factor PRDM10

“…7d, e ). However, published CRISPR screens in mESCs 26 did not support an essential requirement for Eef1d (Supplementary Fig. 8a ), and consistent with this, shRNA-mediated knockdown of Eef1d in mESCs had no observable effect on cell growth (Supplementary Fig.…”

“…7b ). Furthermore, Eif3b has been identified as a positive hit in two genome-wide CRISPR screens for genes essential in mESCs 26 (Supplementary Fig. 8a ), suggesting it is likely to act as a critical mediator of mESC survival downstream of PRDM10.…”

Gene essentiality in cancer cell lines is modified by the sex chromosomes

“…To identify sex-specific mechanisms, we explored gene expression and the effect of loss-of-function mutations on cell survival and proliferation. Recent advances in CRISPR technology have enabled the systematic identification of essential genes necessary for the normal functioning of cells across the genome (Tzelepis et al 2016;Yilmaz et al 2018;Shohat and Shifman 2019). The Achilles project is the largest survey of human gene essentiality (Meyers et al 2017).…”

Gene essentiality in cancer cell lines is modified by the sex chromosomes

“…One approach for identifying sex-specific mechanisms is to explore genes with different functional importance in males and females, such as those essential more to one of the sexes. Recent advances in CRISPR technology have enabled the systematic identification of genes necessary for the normal functioning of cells across the genome (Shohat and Shifman, 2019;Tzelepis et al, 2016;Yilmaz et al, 2018). The Achilles project is the largest survey of human gene essentiality (Meyers et al, 2017).…”