Biology subjects

Jourdon, A.

Publications and source records attributed to Jourdon, A..

6 recordsLinked to original sources

bioRxiv2026

Somatic mutation landscape revealed by non-invasive iPSC derivation from urine cells

Somatic mutations that arise post-zygotically create genetic diversity among normal human cells and provide key insights into human development and aging. Fibroblast-derived induced pluripotent stem cells (iPSCs) have proved to be a useful system for disease modelling; however, due to their clonal nature, iPSC lines carry somatic mutations inherited from the founder cells, raising concerns about their genomic integrity. At the same time, this clonality enables single-cell-level discovery of somatic mutations and the reconstruction of developmental lineages. In living individuals, though, this approach requires invasive biopsies and is limited to skin-derived lineages. Here, we generated 33 urine-derived iPSC lines from four males representing two father- son relationships, performed shallow whole-genome sequencing of the lines and analyzed somatic mutations. Derived iPSCs representing single cells from urine carried a few hundred of somatic single-nucleotide variants per genome, dominated by endogenous, clock-like mutational signatures and lacking environmental imprints such as UV-associated mutations. Copy-number analysis identified somatic CNVs in most of the lines and revealed higher CNV burdens in fathers than in sons, consistent with age-related structural mosaicism. Shared mutations across lines enabled reconstruction of cell lineage phylogenetic trees. In summary, urine-derived iPSCs showed genomic alterations comparable to those in fibroblast-derived iPSC lines and represent a valuable non-invasive alternative for disease modeling. Overall, this study provides the first genome-wide characterization of somatic mutations in urine-derived iPSCs and establishes them as a practical and non-invasive platform for charting somatic mutation landscapes and tracing developmental lineages in living humans.

genomics↗

bioRxiv2024

Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells

The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explored the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identified risk genes expressed in brain organizers and sequential gene regulatory networks across corticogenesis revealing disease-specific critical phases, when NSCs are more vulnerable to gene dysfunctions, and converging signaling across multiple diseases. Moreover, we simulated the impact of risk transcription factor (TF) depletions on different neural cell types spanning the developing human neocortex and observed a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of newly generated autism-affected patient-derived NSCs in vitro revealed recurrent alterations of TFs orchestrating brain patterning and NSC lineage commitment. This work opens new perspectives to explore human brain dysfunctions at the early phases of development. One-sentence summaryThe temporal analysis of gene regulatory networks in human neural stem cells reveals multiple early critical phases associated with cortical disorders and neuropsychiatric traits.

neuroscience↗

bioRxiv2024

Specification of human regional brain lineages using orthogonal gradients of WNT and SHH in organoids

The repertory of neurons generated by progenitor cells depends on their location along antero-posterior and dorso-ventral axes of the neural tube. To understand if recreating those axes was sufficient to specify human brain neuronal diversity, we designed a mesofluidic device termed Duo-MAPS to expose induced pluripotent stem cells (iPSC) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison of single cell transcriptomes with fetal human brain revealed that Duo-MAPS-patterned organoids generated the major neuronal lineages of the forebrain, midbrain, and hindbrain. Morphogens crosstalk translated into early patterns of gene expression programs predicting the generation of specific brain lineages. Human iPSC lines from six different genetic backgrounds showed substantial differences in response to morphogens, suggesting that interindividual genomic and epigenomic variations could impact brain lineages formation. Morphogen gradients promise to be a key approach to model the brain in its entirety.

neuroscience↗

bioRxiv2023

Enhancer-driven regulatory network of forebrain human development provides insights into autism

Cell differentiation is orchestrated by transcription factors (TFs) binding to enhancers, shaping gene regulatory networks that drive neuronal lineage specification. Deciphering these enhancer-driven networks in human forebrain development is essential for understanding the genetic basis of neurodevelopmental disorders. Through integrative epigenomic and transcriptomic analyses of human forebrain organoids derived from 10 individuals with autism spectrum disorder (ASD) and their neurotypical fathers, we constructed a comprehensive enhancer-driven gene regulatory network (GRN) of early neurodevelopment. This GRN revealed hierarchical regulatory transitions guiding neuronal differentiation and was experimentally validated via CRISPR interference (CRISPRi) and loss-of-function analyses. A subnetwork linked ASD-associated transcriptomic alterations to dysregulated TF activity, implicating FOXG1, BHLHE22, EOMES, and NEUROD2 as key regulators of excitatory neuron specification in macrocephalic ASD. These findings suggest that ASD disrupts enhancer-driven regulatory frameworks, altering neuronal cell fate decisions in the developing fetal brain.

genomics↗

bioRxiv2023

Evaluating performance and applications of sample-wise cell deconvolution methods on human brain transcriptomic data

Sample-wise deconvolution methods have been developed to estimate cell-type proportions and gene expressions in bulk-tissue samples. However, the performance of these methods and their biological applications has not been evaluated, particularly on human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk-tissue RNAseq, single-cell/nuclei (sc/sn) RNAseq, and immunohistochemistry. A total of 1,130,767 nuclei/cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expression. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk-tissue or single-cell eQTLs alone. Differential gene expression associated with multiple phenotypes were also examined using the deconvoluted data. Our findings, which were replicated in bulk-tissue RNAseq and sc/snRNAseq data, provided new insights into the biological applications of deconvoluted data.

genomics↗

bioRxiv2022

ASD modelling in organoids reveals imbalance of excitatory cortical neuron subtypes during early neurogenesis

There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using cortical organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with idiopathic ASD and their unaffected fathers in thirteen families. Alterations in the transcriptome suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between the excitatory neurons of the dorsal cortical plate and other lineages such as the early-generated neurons from the putative preplate. The imbalance stemmed from a divergent expression of transcription factors driving cell fate during early cortical development. While we did not find probands genomic variants explaining the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and developmental transcriptome in idiopathic ASD.

neuroscience↗