Somatic mutations alter the differentiation outcomes of iPSC-derived neurons

Puigdevall, Pau; Jerber, Julie; Danecek, Petr; Castellano, Sergi; Kilpinen, Helena

doi:10.1016/j.xgen.2023.100280

Cited by 6 publications

(4 citation statements)

References 57 publications

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“…The variability in escape from XCI has been previously associated with key properties of hiPSCs, such as the differentiation ability 5,35 . Intriguingly, we found that BCOR, an inactive gene in humans where deleterious mutations are associated with increased proliferation and reduced differentiation ability 22 , escaped readily in female hiPSCs suggesting that the escape could be advantageous for the stem cell properties of the cells. Conversely, we found several dominant disease-linked genes whose expression was changed by escape from XCI and suggest that these modifying effects can complicate biological modeling if not addressed appropriately.…”

Section: Discussionmentioning

confidence: 86%

“…In addition, we observed clusters of genes, such as GRPR, TXLNG, RBBP7 and DYNLT3, RPGR, and BCOR, that are inactive in humans but frequently escaped in the hiPSCs. Recently deleterious mutations in BCOR were associated with reduced differentiation capacity in pluripotent stem cells 22 . Taken together, this suggested that some epigenetic marks underlying XCI may be subject to removal during reprogramming that have roles in the stem cell state and differentiation capacity of the hiPSCs.…”

Section: Erosion Of XCI Affects Predominantly Genes That Escape In Hu...mentioning

confidence: 99%

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X-chromosome inactivation in human iPSCs provides insight into escape-regulated gene expression

Topa,

Benoit-Pilven,

Tukiainen

et al. 2023

Preprint

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Epigenetic variation in the X chromosome inactivation (XCI) of human induced pluripotent stem cells (hiPSCs) can impact their ability to accurately model biological sex biases. However, the gene-wise landscape of escape from XCI remains unresolved in female hiPSCs. To characterize the patterns of escape from inactivation, we performed a systematic survey of allele specific expression (ASE) in 165 female hiPSC lines. The analysis revealed that the escape from XCI was non-random and affected primarily genes that escape also in human tissues. However, individual genes and cell lines varied in the frequency and degree of escape. The escape increased gradually after modest decrease ofXISTin cultures, whose loss is commonly used to mark lines with eroded XCI. We identified three clusters of female lines at different stages of XCI. The increased degree of escape from XCI amplified female-biased expression and reduced male-female differences in genes with male-biased expression in the X chromosome. In autosomes, the increased escape modified genuine sex differences in a dose-dependent way suggesting that escape from XCI directly regulated autosomal gene expression. The variation in escape was sufficient to compensate for a dominant loss of function effect in several disease genes. The study presents a comprehensive view of escape from XCI in hiPSCs and emphasizes the need to monitor the XCI status at gene level for disease modeling. It further suggests that the uncommon and variable escape in hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans.

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Section: Discussionmentioning

confidence: 86%

Section: Erosion Of XCI Affects Predominantly Genes That Escape In Hu...mentioning

confidence: 99%

X-chromosome inactivation in human iPSCs provides insight into escape-regulated gene expression

Topa,

Benoit-Pilven,

Tukiainen

et al. 2023

Preprint

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“…Our detailed genetic analyses of the used cell lines revealed other mutations that had naturally arisen in these cell lines (Supplementary Table 4), including a point mutation in the BCL6-interacting corepressor BCOR (BCOR L1673F ). BCOR mutations have been previously observed in human induced pluripotent stem cell cultures 95,96 and NB patients with BCOR mutations exhibit a high frequency of CNAs 89 . BCOR mutations have also been reported together with CNAs in other cancers, e.g., retinoblastoma 97 .…”

Section: Discussionmentioning

confidence: 91%

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

Saldana-Guerrero

Montaño-Gutierrez

Hafemeister

et al. 2022

Preprint

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Early childhood tumours are thought to arise from transformed embryonic cells, which often carry large copy number variants (CNVs). However, it remains unclear how CNVs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ human embryonic stem cell (hESC) differentiation to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNVs impair the specification of hESC-derived trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. Overexpression of MYCN, whose amplification co-occurs with CNVs in NB, exacerbates the differentiation block, and enables tumourigenic cell proliferation. We find links between disrupted cell states in vitro and tumour cells and connect these states with stepwise disruption of developmental transcription factor networks. Together, our results chart a possible route to NB and provide a mechanistic framework for the CNV-driven initiation of embryonal tumours.

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“…This lack of consistency is likely due to genetic or epigenetic differences between cell lines that can lead to different baseline expression of or susceptibility to WNT and other developmental signaling pathways 45 . Recent work has evaluated somatic mutation effects on neuronal differentiation competency from different iPSC lines and provided genotyping resources for hundreds of hESC lines 58,59 . These resources, together with high-throughput and systematic screens will help understand the nature of differences between hPSC lines to generate human neural tissues.…”

Section: Discussionmentioning

confidence: 99%

Decoding morphogen patterning of human neural organoids with a multiplexed single-cell transcriptomic screen

Sanchís-Calleja,

Jain,

et al. 2024

Preprint

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Morphogens, secreted signaling molecules that direct cell fate and tissue development, are used to instruct neuroepithelium to differentiate towards discrete brain region identities. Neural tissues derived from pluripotent stem cells in vitro (neural organoids) provide new models for studying brain region development, however, we lack a comprehensive survey of how the developing human neuroepithelium responds to morphogen cues. Here, we produce a detailed map of morphogen-induced effects on the axial and regional specification of human neural organoids using a multiplexed single-cell transcriptomics screen. We find that the timing, concentration, and combination of morphogens strongly influence organoid cell type and regional composition, and that cell line and neural induction method strongly impact the response to a given morphogen condition. We apply concentration gradients in microfluidic chips or a range of static concentrations in multi-well plates to explore how human neuroepithelium interprets morphogen concentrations and observe similar dose-dependent induction of patterned domains in both scenarios. Altogether, we provide a detailed resource that supports the development of new regionalized neural organoid protocols and enhances our understanding of human central nervous system patterning.

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Somatic mutations alter the differentiation outcomes of iPSC-derived neurons

Cited by 6 publications

References 57 publications

X-chromosome inactivation in human iPSCs provides insight into escape-regulated gene expression

X-chromosome inactivation in human iPSCs provides insight into escape-regulated gene expression

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

Decoding morphogen patterning of human neural organoids with a multiplexed single-cell transcriptomic screen

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