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Single-cell RNA-seq reveals differentiation hierarchy of normal human bone marrow and a distinct transcriptome signature of aneuploid cells

ABSTRACT: In order to get a better understanding of the gene signature of aneuploid cells, we applied single cell RNA sequencing on human bone marrow cells from healthy donors and patients with bone marrow failure and cytogenetic abnormalities. We chacterized normal hemaopoiesis as binary differentiation and identified aneuploid cells from patient samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99095 | GEO | 2017/10/13

SECONDARY ACCESSION(S): PRJNA387283

REPOSITORIES: GEO

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Biallelic loss-of-function mutations in MAD1 result in systemic inflammation, clonal selection of aneuploid cells and high tumor susceptibility

Project description:Aneuploidy is a frequent feature of tumor cells. Yet, germline mutations leading to chromosomal instability are less frequent and are typically found in patients with mosaic variegated aneuploidy (MVA). We describe here novel germline biallelic loss-of-function mutations in MAD1L1, a gene that encodes the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with microcephaly and developmental delay. The patient developed a constelation of benign and malignant neoplasias derived from the three embryonic layers, some of them such as pilomatrixoma, bone tumors enchondromas and multinodular goiter rarely described in MVA. Cytogenetic and single-cell DNA analysis of peripheral blood cells detected ~35% of aneuploid cells with a variety of random gains of chromosomes. Functional studies demonstrated deficient SAC responses in the absence of MAD1 in mutant lymphocytes. Transcriptomic studies of peripheral blood cells at the single cell level suggested inhibition of protein synthesis, and increased antigen presentation and cytokine signaling in aneuploid T-cells. These pathways were also deregulated in euploid cells from the patient suggesting an immflamation-like, systemic response to chromosomal instability. In addition, single cell RNA-seq analysis detected clonal expansions affecting chromosomes 12 and 18 in specific B-cell and T-cell populations without evidence of hematopoietic neoplasias. These data point to MAD1L1 as a new gene mutated in MVA, and suggest that clonal expansion of minor aneuploid cell populations can be detected in pro-tumoral stages using single-cell technologies.

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Project description:Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, whether and how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene expression patterns have been reported: an environmental stress response (ESR) and a “common aneuploidy gene-expression” (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate and bring clarity to this controversy. We show that the CAGE signature is not an aneuploidy-specific gene expression signature but is the result of euploid control cells, but not aneuploid cells, having grown into stationary phase. Because growth into stationary phase is amongst the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells are found to exhibit the ESR. We further show that the ESR causes a selective loss of ribosomes in aneuploid cells, providing an explanation for the decreased cellular density in aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than a CAGE signature, in response to aneuploidy-induced cellular stresses that results in selective ribosome loss.

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Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells

Project description:Aneuploidy, an abnormal chromosome composition, results in a stoichiometric imbalance of protein complexes, which jeopardizes the fitness of aneuploid cells. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, a phenomenon known as dosage compensation. However, the molecular mechanisms involved in dosage compensation in human cells – and whether they can be targeted to selectively kill aneuploid cancer cells – remain unknown. Here, we addressed this question via molecular dissection of multiple diploid vs. aneuploid cell models. Using genomic and functional profiling of a novel isogenic system of RPE1-hTERT cells with various degrees of aneuploidy, we found that aneuploid cells cope with both transcriptional burden and proteotoxic stress. At the mRNA level, aneuploid cells increased RNA synthesis, but concomitantly elevated several RNA degradation pathways, in particular the nonsense-mediated decay (NMD) and the microRNA-mediated mRNA silencing pathways. Consequently, aneuploid cells were more sensitive to the genetic or chemical perturbation of several key components of these RNA degradation pathways. At the protein level, aneuploid cells experienced proteotoxic stress, resulting in reduced translation and increased protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, confirming that both non-transformed and transformed cells alter their RNA and protein metabolism in order to adapt to the aneuploid state. Our results reveal that aneuploid cells are dependent on the over- or under-activation of several nodes along the gene expression process, identifying these pathways as clinically-actionable vulnerabilities of aneuploid cells.

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