HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

Sanchez-Vasquez, Estefania; Bronner, Marianne E.; Zernicka-Goetz, Magdalena

doi:10.1101/2023.09.04.556218

Cited by 4 publications

References 86 publications

(212 reference statements)

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Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Regin

Lei

Deckersberg

et al. 2022

Preprint

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Aneuploidy is present in about 80% of human preimplantation embryos and is thought to largely explain our relatively low fertility. However, the percentage of aneuploid cells decreases progressively during the early cleavages and chromosomally mosaic human embryos have been shown to result in healthy newborns with normal karyotypes. These observations imply a selective loss of aneuploid cells, but the underlying mechanisms are not yet fully understood. Here, we show that, while aneuploid embryos had lower cell numbers in both trophectoderm (TE) and inner-cell-mass (ICM), the effect of aneuploidy was cell-type dependent. Aneuploid TE presented transcriptomic signatures of DNA-damage, p53-signalling and apoptosis. Immunostaining of whole embryos showed that aneuploidy results in increased proteotoxic stress, autophagy, DNA damage-mediated activated p53 and subsequent apoptosis in the TE only. In the ICM, aneuploidy impaired primitive endoderm differentiation. Our findings explain why fully aneuploid embryos fail to further develop and shed light on the mechanisms by which aneuploid cells are removed from mosaic embryos.

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Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Regin

Lei

Deckersberg

et al. 2022

Preprint

View full text Add to dashboard Cite

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Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Regin,

Lei,

Couvreu De Deckersberg

et al. 2024

eLife

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About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids have shown that aneuploid cells show proteotoxic stress, autophagy and p53 activation and that they are eliminated from the epiblast by apoptosis while being rather tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. In this study we investigated the cellular consequences of aneuploidy in a total of 85 human blastocysts. RNA-sequencing of trophectoderm cells showed transcriptional signatures of a deregulated p53 pathway and apoptosis, which was proportionate to the level of chromosomal imbalance. Immunostaining revealed that aneuploidy triggers proteotoxic stress, autophagy and apoptosis in aneuploid embryos. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, it appeared that aneuploidy impairs the second lineage segregation and primitive endoderm formation in particular. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to removal of aneuploid cells from mosaic embryos. This hypothesis needs further study as we did not analyse chromosomal mosaic embryos. Finally, we demonstrated clear differences with previous findings in the mouse, emphasizing the need for human embryo research to understand the consequences of aneuploidy.

show abstract

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Regin,

Lei,

De Deckersberg

et al. 2024

Preprint

View full text Add to dashboard Cite

About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids have shown that aneuploid cells show proteotoxic stress, autophagy and p53 activation and that they are eliminated from the epiblast by apoptosis while being tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. In this study we investigated the cellular consequences of aneuploidy in a total of 125 human blastocysts. RNA-sequencing of trophectoderm cells showed transcriptional signatures of activated p53 pathway and apoptosis, which was proportionate to the level of chromosomal imbalance. Immunostaining corroborated that aneuploidy triggers proteotoxic stress, autophagy, p53-signalling, and apoptosis independent from DNA damage. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, it appeared that aneuploidy impaired the second lineage segregation, particularly primitive endoderm formation. This might be reinforced by retention of NANOG in aneuploid embryos. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to removal of aneuploid cells from mosaic embryos. This hypothesis needs further study as we did not analyze chromosomal mosaic embryos. Finally, we demonstrated a few differences with previous findings in the mouse, emphasizing the need for human embryo research to understand the consequences of aneuploidy.

show abstract

HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

Cited by 4 publications

References 86 publications

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

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