The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Khan, Chaitali; Baker, Nicholas E.

doi:10.1101/2022.06.06.494998

Cited by 2 publications

(1 citation statement)

References 107 publications

(193 reference statements)

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“…Elevated expression of Xrp1 in Rp mutant Drosophila cells restricts translation, cellular growth, and mosaic organismal development 123 . Although there is no direct homolog of Xrp1 in humans, the human bZip domain protein most similar to the Drosophila Xrp1 is DNA Damage Induced Transcript 3 (DDIT3 or CHOP) 130 , and also mediates multiple functions of p53 131 , which we found upregulated at the regulon level in aneuploid cells post-EGA, aligning with the cell competition model of Drosophila . DDIT3 is known as a multifunctional transcription factor in the ER unfolded protein response, and fulfils an essential role in inducing cell cycle arrest and apoptosis when the UPR salvage pathway fails.…”

Section: Discussionsupporting

confidence: 80%

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Gallardo

Sifrim

Chappell

et al. 2023

Preprint

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The frequent acquisition of genomic abnormalities in human preimplantation embryos is a leading cause of pregnancy loss, but does not necessarily prohibit healthy offspring. However, the impact of genomic abnormalities on cellular states and development of the early human embryo remains largely unclear. Here, we characterise aneuploidy and reconstruct gene regulatory networks in human preimplantation embryos, and investigate gene expression and developmental perturbations instigated by aneuploidy using single-cell genome-and-transcriptome sequencing (G&T-seq). At the genomic level, we show that acquired numerical and structural chromosomal aberrations are frequent across all stages of early embryogenesis and in all cell lineages. At the transcriptome level, we identify regulators of cell identity and uncover a network of 248 transcription factors from 10 major gene regulatory modules that characterise the distinct lineages of human preimplantation embryos. By integrating single-cell DNA- with RNA-information, we unveil how expression levels are affected by losses or gains of the corresponding genes in embryonic cells across human preimplantation development, as well as how copy-number aberrant transcription factor genes perturb the expression of their cognate target genes in euploid regions. Furthermore, we reveal a majority of aneuploid cells show a developmental delay and reduced fitness, indicating cell competition within the mosaic diploid-aneuploid embryo, which may contribute to selection against aneuploid cells and the birth of healthy offspring from mosaic diploid-aneuploid embryos. In summary, our multi-modal analyses provide unprecedented insights into early human embryo development.

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Section: Discussionsupporting

confidence: 80%

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Gallardo

Sifrim

Chappell

et al. 2023

Preprint

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Single cell transcriptomics of X-ray irradiatedDrosophilawing discs reveals heterogeneity related to cell-cycle status and cell location

Cruz,

Sun,

Verbeke

et al. 2024

Preprint

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Even seemingly homogeneous populations of cells can express phenotypic diversity in response to environmental changes. Thus, the effects of X-ray irradiation on tissues composed of diverse cell types is likely to be complex. We have used single-cell RNA sequencing to study the effects of X-ray radiation on the wing-imaginal disc ofDrosophila, a relatively simple tissue that is mostly composed of epithelial cells. Transcriptomic clustering of cells collected from the wing disc generates clusters that are mainly grouped based on cell location in the proximodistal axis. To quantify heterogeneity of gene expression among clusters, we adapted a metric used to study market concentration, the Herfindahl-Hirschman Index. We show that genes involved in DNA damage repair, alleviation of reactive oxygen species, cell-cycle progression, and apoptosis are expressed relatively uniformly. In contrast, genes encoding a subset of ligands, notably cytokines that activate the JAK/STAT pathway, transcription factors implicated in regeneration such as Ets21C, and some signaling proteins are expressed in more restricted territories. Several of these genes are still expressed in a p53-dependent manner indicating that regional and radiation-induced factors combine to regulate their expression. We similarly examined heterogeneity within territories by using a clustering approach based on cell-cycle gene expression. Using this method, we identified a subpopulation characterized by high levels oftribblesexpression that is mostly found in irradiated discs. Remarkably, this subpopulation accounts for a considerable fraction of radiation-induced gene expression, indicating that cellular responses are non-uniform even within territories. Thus, both inter-regional and intra-regional heterogeneity are important features of tissue responses to X-ray radiation.

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The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Cited by 2 publications

References 107 publications

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Single cell transcriptomics of X-ray irradiatedDrosophilawing discs reveals heterogeneity related to cell-cycle status and cell location

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