Developmental Gene Expression Differences between Humans and Mammalian Models

Cardoso-Moreira, Margarida; Sarropoulos, Ioannis; Velten, Britta; Mort, Matthew; Cooper, David Neil; Huber, Wolfgang; Kaessmann, Henrik

doi:10.1016/j.celrep.2020.108308

Cited by 57 publications

(31 citation statements)

References 64 publications

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“…Overall, our observations reveal that inclusion frequencies of microexons increase during development and suggest a prominent role of microexons in early brain development. This latter notion is in agreement with microexons being neuron specific and predominantly involved in neurogenesis 37,38 , and with the misregulation of microexons being associated with autism 37 , a disorder associated with genes predominantly expressed in early brain development 39,40 . Illustrations are based on a new exon in APP (Extended Data Fig.…”

Section: Exon Usage Across Developmentsupporting

confidence: 73%

Alternative splicing during mammalian organ development

et al. 2021

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Alternative splicing (AS) is pervasive in mammalian genomes, yet cross-species comparisons have been largely restricted to adult tissues and the functionality of most AS events remains unclear. We assessed AS patterns across pre- and postnatal development of seven organs in six mammals and a bird. Our analyses revealed that developmentally dynamic AS events, which are especially prevalent in the brain, are substantially more conserved than nondynamic ones. Cassette exons with increasing inclusion frequencies during development show the strongest signals of conserved and regulated AS. Newly emerged cassette exons are typically incorporated late in testis development, but those retained during evolution are predominantly brain specific. Our work suggests that an intricate interplay of programs controlling gene expression levels and AS is fundamental to organ development, especially for the brain and heart. In these regulatory networks, AS affords substantial functional diversification of genes through the generation of tissue- and time-specific isoforms from broadly expressed genes.

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Section: Exon Usage Across Developmentsupporting

confidence: 73%

Alternative splicing during mammalian organ development

et al. 2021

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“…For one, it is not fully clear whether CM maturation trends must be preserved across species. While recent results from Cardoso-Moreira indicate that developmental trends between species are often divergent (65), the results from Uosaki et al suggest that CM maturation in particular is relatively well-preserved (66). Both sets of studies were done using bulk cardiac data, and scRNA-seq data is currently unavailable for human perinatal timepoints.…”

Section: Discussionmentioning

confidence: 99%

Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes

Kannan¹,

Miyamoto

Lin

et al. 2021

Preprint

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A primary limitation in the clinical application of pluripotent stem cell derived cardiomyocytes (PSC-CMs) is the failure of these cells to achieve full functional maturity. In vivo, cardiomyocytes undergo numerous adaptive changes during perinatal maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. To date, however, the precise mechanisms by which directed differentiation differs from endogenous development, leading to consequent PSC-CM maturation arrest, are unknown. The advent of single cell RNA-sequencing (scRNA-seq) has offered great opportunities for studying CM maturation at single cell resolution. However, perinatal cardiac scRNA-seq has been limited owing to technical difficulties in the isolation of single CMs. Here, we used our previously developed large particle fluorescence-activated cell sorting approach to generate an scRNA-seq reference of mouse in vivo CM maturation with extensive sampling of perinatal time periods. We subsequently generated isogenic embryonic stem cells and created an in vitro scRNA-seq reference of PSC-CM directed differentiation. Through trajectory reconstruction methods, we identified a perinatal maturation program in endogenous CMs that is poorly recapitulated in vitro. By comparison of our trajectories with previously published human datasets, we identified a network of nine transcription factors (TFs) whose targets are consistently dysregulated in PSC-CMs across species. Notably, we demonstrated that these TFs are only partially activated in common ex vivo approaches to engineer PSC-CM maturation. Our study represents the first direct comparison of CM maturation in vivo and in vitro at the single cell level, and can be leveraged towards improving the clinical viability of PSC-CMs.Significance StatementThere is a significant clinical need to generate mature cardiomyocytes from pluripotent stem cells. However, to date, most differentiation protocols yield phenotypically immature cardiomyocytes. The mechanisms underlying this poor maturation state are unknown. Here, we used single cell RNA-sequencing to compare cardiomyocyte maturation pathways in endogenous and pluripotent stem cell-derived cardiomyocytes. We found that in vitro, cardiomyocytes fail to undergo critical perinatal gene expression changes necessary for complete maturation. We found that key transcription factors regulating these changes are poorly expressed in vitro. Our study provides a better understanding of cardiomyocyte maturation both in vivo and in vitro, and may lead to improved approaches for engineering mature cardiomyocytes from stem cells.

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“…While it is understandable that studies have focused on Wnt4 since the first paper describing its role in ovary determination in mice [Vainio et al, 1999], a more systematic analysis of the role of other Wnt genes in sex determination is clearly warranted. Indeed, studies of human embryonic gonads do not detect sex differences in WNT4 expression during the sex-determining period [Mamsen et al, 2017;Cardoso-Moreira et al, 2020]. Wnt2b is of particular interest for further studies because it is the only Wnt gene that displays a conserved pattern of sexually dimorphic expression between snapping turtle, red-eared slider turtle, and human.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Turnover in Wnt Gene Expression but Conservation of Wnt Signaling during Ovary Determination in a TSD Reptile

Rhen

Even

Brenner

et al. 2021

Sex Dev

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Temperature-dependent sex determination (TSD) is a well-known characteristic of many reptilian species. However, the molecular processes linking ambient temperature to determination of gonad fate remain hazy. Here, we test the hypothesis that Wnt expression and signaling differ between female- and male-producing temperatures in the snapping turtle Chelydra serpentina. Canonical Wnt signaling involves secretion of glycoproteins called WNTs, which bind to and activate membrane bound receptors that trigger β-catenin stabilization and translocation to the nucleus where β-catenin interacts with TCF/LEF transcription factors to regulate expression of Wnt targets. Non-canonical Wnt signaling occurs via 2 pathways that are independent of β-catenin: one involves intracellular calcium release (the Wnt/Ca2+ pathway), while the other involves activation of RAC1, JNK, and RHOA (the Wnt/planar cell polarity pathway). We screened 20 Wnt genes for differential expression between female- and male-producing temperatures during sex determination in the snapping turtle. Exposure of embryos to the female-producing temperature decreased expression of 7 Wnt genes but increased expression of 2 Wnt genes and Rspo1 relative to embryos at the male-producing temperature. Temperature also regulated expression of putative Wnt target genes in vivo and a canonical Wnt reporter (6x TCF/LEF sites drive H2B-GFP expression) in embryonic gonadal cells in vitro. Results indicate that Wnt signaling was higher at the female- than at the male-producing temperature. Evolutionary analyses of all 20 Wnt genes revealed that thermosensitive Wnts, as opposed to insensitive Wnts, were less likely to show evidence of positive selection and experienced stronger purifying selection within TSD species.

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Developmental Gene Expression Differences between Humans and Mammalian Models

Cited by 57 publications

References 64 publications

Alternative splicing during mammalian organ development

Alternative splicing during mammalian organ development

Trajectory reconstruction identifies dysregulation of perinatal maturation programs in pluripotent stem cell-derived cardiomyocytes

Evolutionary Turnover in Wnt Gene Expression but Conservation of Wnt Signaling during Ovary Determination in a TSD Reptile

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