Haploid Human Embryonic Stem Cells: Half the Genome, Double the Value

Yilmaz, Atilgan; Peretz, Mordecai; Sagi, Ido; Benvenisty, Nissim

doi:10.1016/j.stem.2016.10.009

Cited by 29 publications

(24 citation statements)

References 10 publications

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“…1A). This observation is consistent with previous studies using haploid cells that have linked this action to the "diploidization" of the haploids (19). To specifically analyze the growth properties of haploid HAP1 cells, haploid and diploid cell populations were FACS-sorted and grown independently.…”

Section: Resultssupporting

confidence: 88%

“…Although this phenomenon has been considered a consequence of diploidization (19), here we have shown that it is due to reduced fitness and growth properties of haploid cells, which are outcompeted by the diploid cells existing in these cultures. At least in mammals, this reduced fitness is explained in part by the activation of a p53-dependent cytotoxic response, associated with difficulties arising during the segregation of haploid DNA content.…”

Section: Discussionmentioning

confidence: 60%

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A p53-dependent response limits the viability of mammalian haploid cells

Olbrich

Mayor‐Ruiz

Vega-Sendino

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The recent development of haploid cell lines has facilitated forward genetic screenings in mammalian cells. These lines include nearhaploid human cell lines isolated from a patient with chronic myelogenous leukemia (KBM7 and HAP1), as well as haploid embryonic stem cells derived from several organisms. In all cases, haploidy was shown to be an unstable state, so that cultures of mammalian haploid cells rapidly become enriched in diploids. Here we show that the observed diploidization is due to a proliferative disadvantage of haploid cells compared with diploid cells. Accordingly, single-cell-sorted haploid mammalian cells maintain the haploid state for prolonged periods, owing to the absence of competing diploids. Although the duration of interphase is similar in haploid and diploid cells, haploid cells spend longer in mitosis, indicative of problems in chromosome segregation. In agreement with this, a substantial proportion of the haploids die at or shortly after the last mitosis through activation of a p53-dependent cytotoxic response. Finally, we show that p53 deletion stabilizes haploidy in human HAP1 cells and haploid mouse embryonic stem cells. We propose that, similar to aneuploidy or tetraploidy, haploidy triggers a p53-dependent response that limits the fitness of mammalian cells.haploidy | embryonic stem cells | p53 | HAP1 | chromosome segregation T he main advantage of yeast as a model organism for genetic studies is the availability of haploid cells, so that the mutation of a single allele can suffice to reveal a phenotype. This approach has been of enormous importance for biomedical research in recent decades, as exemplified by the number of Nobel Prizes awarded to discoveries that used yeast as a model system, including the discovery of autophagy, telomeres, and the cell cycle (1). In any case, there are questions intrinsic to mammalian biology, such as stemness or differentiation, that are difficult to address using yeast as a model, and that could be answered by the availability of mammalian haploid cell lines.

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Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 60%

A p53-dependent response limits the viability of mammalian haploid cells

Olbrich

Mayor‐Ruiz

Vega-Sendino

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Data on essential genes in haploid hESCs was obtained from Yilmaz et al (Yilmaz et al 2016); data on essential genes in human cancer cell lines was obtained from Yusa et al (Tzelepis et al 2016) and Wang et al (Wang et al 2017). Genes essential only in ESCs were defined as genes essential in mESCs and hESCs (FDR corrected P < 0.05) but not essential in more than one of the 11 human cancer cell lines.…”

Section: Comparison Of Essential Genes Between Mescs Hescs and Cancementioning

confidence: 99%

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Shohat

Shifman

2019

Preprint

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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.

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“…Aside from the value of haploid human ESCs in understanding human development, they may also play a role in future procedures of reproductive medicine, providing a putative source for haploid gametes. Yet, the most obvious usefulness of haploid human ESCs is in the context of haploid genetics, enabling simplified loss-of-function screening on a human genetic background (for a broader view on the biomedical applications of haploid human ESCs, see Yilmaz et al, 2016). We anticipate that haploid human ESCs will serve as useful tools for studying human genetics, development, and pathology in a wide range of research fields.…”

Section: Discussionmentioning

confidence: 99%

Haploidy in Humans: An Evolutionary and Developmental Perspective

Sagi

Benvenisty

2017

Developmental Cell

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Although haploidy has not been observed in vertebrates, its natural occurrence in various eukaryotic species that had diverged from diploid ancestors suggests that there is an innate capacity for an organism to regain haploidy and that haploidy may confer evolutionary benefits. Haploid embryonic stem cells have been experimentally generated from mouse, rat, monkey, and humans. Haploidy results in major differences in cell size and gene expression levels while also affecting parental imprinting, X chromosome inactivation, and mitochondrial metabolism genes. We discuss here haploidy in evolution and the barriers to haploidy, in particular in the human context.

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Haploid Human Embryonic Stem Cells: Half the Genome, Double the Value

Cited by 29 publications

References 10 publications

A p53-dependent response limits the viability of mammalian haploid cells

A p53-dependent response limits the viability of mammalian haploid cells

Genes essential for embryonic stem cells are associated with neurodevelopmental disorders

Haploidy in Humans: An Evolutionary and Developmental Perspective

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