Biology subjects

Bramoulle, A.

Publications and source records attributed to Bramoulle, A..

3 recordsLinked to original sources

bioRxiv2023

PSEN1-M146V and PSEN1-A246E mutations associated with Alzheimers disease impair proper microglia differentiation

Genetic variants associated with the late onset of Alzheimers disease (AD), were correlated with genes known to be expressed in microglia, suggesting for an AD-genetic component directly influencing microglia behavior. Instead, the role of the familial AD (fAD) genetic mutations was systematically studied from the angle of the Amyloid-Beta pathway; leaving their participation in microglia homeostasis unexplored. Here we demonstrate that two previously described fAD-related PSEN1 mutations directly impair proper microglia differentiation. While human induced pluripotent stem cells harboring the PSEN1-M146V mutation did not give rise to hematopoietic precursor (HPC) intermediate during microglia differentiation, a PSEN1-A246E mutant line managed to produce HPCs, but died within the first days of microglia differentiation. Detailed transcriptomics/epigenomics and functional assays revealed the setup of a pro-apoptotic program in the PSEN1-A246E mutant, which was circumvented when HPCs were grafted in brain organoids (BORGs). Microglia obtained in BORGs presented preferentially pro-inflammatory signatures, further supported by their correlation with recent data providing a detailed stratification of the various microglia populations within AD-patient samples. Overall, this study contributes to reconsider the influence of the previously identified familial mutations in the homeostasis of this immune component of the central nervous system.

neuroscience↗

bioRxiv2023

A 3-dimensional molecular cartography of human cerebral organoids revealed by double-barcoded spatial transcriptomics

Spatially-resolved transcriptomics is revolutionizing our understanding of complex tissues, but their current use for the exploration of a few sections is not representative of their 3-dimensional architecture. In this work we present a low-cost strategy for manufacturing molecularly double-barcoded DNA arrays, enabling large-scale spatially-resolved transcriptomics studies. We applied this technique to spatially resolve gene expression in several human brain organoids, including the reconstruction of a 3-dimensional view from multiple consecutive sections, revealing gene expression divergencies throughout the tissue.

systems biology↗

bioRxiv2022

A synergistic activation of RARb and RARg nuclear receptors restores cell-types specialization during stem cells differentiation by hijacking RARa-controlled program

How cells respond to different external cues to develop along defined cell lineages to form complex tissues is a major question in systems biology. Here, we investigated the potential of retinoic acid receptor (RARs)-selective synthetic agonists to activate the gene-regulatory programs driving cell specialization during nervous tissue formation from P19 stem cells. Specifically, we found that the synergistic activation of the RAR{beta} and RAR{gamma} by selective ligands (BMS641 or BMS961) induces cell maturation to specialized neuronal subtypes, as well as to astrocytes and oligodendrocyte precursors. Using RAR istoype knockout lines exposed to RAR-specific agonists, interrogated by global transcriptome landscaping and in silico modeling of transcription regulatory signal propagation, revealed major RAR-driven gene programs essential for optimal neuronal cell specialization, and hijacked by the synergistic activation of the RAR{beta} and RAR{gamma} receptors. Overall, this study provides a systems biology view of the gene programs accounting for the previously observed redundancy between RAR receptors, paving the way towards their potential use for directing cell specialization during nervous tissue formation.

molecular biology↗