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Carlos PARRAS

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Photo de Carlos PARRAS

Carlos PARRAS

Title: Project Sponsor, PhD, CR1

Function: PI

Affiliated entities INSERM

Biography
Biography

Carlos Parras is an expert in molecular and genetic neurobiology (CR1 at INSERM since 2008). He completed his PhD in neurobiology using Drosophila as a genetic model at the Severo Ochoa Molecular Biology Centre of the Autonomous University of Madrid (1997). He completed a postdoctoral fellowship in the laboratory of F. Guillemot on mouse genetic models studying the engagement of neural stem cells in different neural subtypes in Strasbourg (IGBMC, 1998-2003) and London (NIMR, 2003-2006). He obtained a AVENIR grant to develop his research group at the Salpêtrière hospital (Inserm U711, 2006-2011), and joined the group of JL Thomas & B Zalc (2009) focusing on the transcriptional regulation of oligodendrogenesis, using genetically modified mouse models and focal de/remyelination as well as the analysis of post-mortem brain samples of patients with multiple sclerosis. He demonstrated the role of Ascl1, a key neurogenic transcription factor, in the specification and differentiation of oligodendrocytes during myelination and remyelination. His recent research, characterizing the common genetic targets of Ascl1/Olig2, has shown the important role in oligodendrocyte differentiation during myelination and remyelination of chromatin remodelers CHD7 and CHD8, whose haploinsufficiency in man leads to CHARGE syndrome and autism spectrum disorder, respectively. He was awarded the Marie-Ange Bouvet Labruyère prize by the Fondation de France in February 2018 for his work. His lab has established genome-wide approaches to study transcription regulation in brain cells, focusing on oligodendrocytes as a model system, to study cooperation between transcription factors (such as Ascl1, Olig2, and Sox10) and chromatin remodeling (Chd7 and Chd8) in transcription regulation and cell destinies (generation, proliferation, survival, and differentiation) during development. and pathology (including autism, premature birth and multiple sclerosis). In 2019, he joined the "Brain Development" team led by B Hassan, and contributed to projects on the development of mouse brain and human cultures mimicking corticogenesis from induced pluripotent stem cells (iPSCs), in particular on the role of human APP during cortical neurogenesis. His group has optimized protocols and analyses for pangenomic studies at the transcriptomic level (RNA-seq and single-cell) but also at the chromatin level (ChIP-seq for transcription regulators and brands of regulatory histones, and ATAC-seq).

Research
Research

His group's current projects include:

  • Transcriptional regulation of gliogenesis: a play between transcription factors and chromatin remodelers
    Oligodendrocytes (OLs) are myelin-forming cells of the central nervous system that envelop axons and allow saltatory conduction of action potentials. These cells arise from differentiation of oligodendrocyte precursor cells (OPCs), which requires extensive genetic reprogramming involving transcription factors but also chromatin remodelers. We have previously demonstrated the role of two of them, Chd7 and Chd8, in aspects of OPC biology, such as differentiation, proliferation, and survival. Both are implicated in diseases affecting brain development, with mutations in the genes Chd7 and Chd8 causing respectively CHARGE syndrome and autism spectrum disorders (ASD). In this study, we used the CPOs as a model to understand the specificity of Chd7 and Chd8 and their compensatory effect on each other. To this end, we examine the OPC and transcription deregulation (RNA-seq) processes caused by the loss of each or both factors. Using binding profiles (ChIP-seq) of these factors, we seek to understand their direct regulation in OPC biology. This study will lead to a better understanding of the molecular mechanisms controlled by two chromatin remodelers involved in brain development and disease.
  • Characterization of the molecular mechanisms of Tns3 function in oligodendroglies
    Multiple sclerosis (MS) is a neurological disease characterized by a loss of oligodendrocytes, the myelinating cells of the central nervous system. Despite recent advances in preventing the immune system from attacking oligodendrocytes, effective remyelination therapies are still lacking. In MS, spontaneous remyelination from oligodendrocyte precursor cells (OPCs) present throughout the brain is ineffective and decreases with age. The observation that POCs are present in the demyelinating lesions of MS but do not differentiate into myelinating cells suggests that induction of POC differentiation is a critical event for successful remyelination. We recently identified Tns3 (Tensin 3) as a target gene for Ascl1 and Olig2, two key oligodendrogenic transcription factors, and showed that Tns3 is strongly induced at the time of oligodendrocyte differentiation while it is downregulated in mature oligodendrocytes, providing a good marker for immature oligodendrocytes. Using Tns3Tns3-V5 knock-in mice, we found that the Tns3 protein labelled at the C-terminal end with the small epitope V5 was detected specifically in oligodendrocytes, where it was mainly restricted to the immature OL stage, being localized in the perinuclear cytoplasm and cellular processes. This pattern of expression is also found during remyelination of adult brain after LPC injection, where Tns3 is present in newly formed OL. Therefore, Tns3 is a new marker for immature LOs. Loss of function (LOF) in vivo of Tns3 by CRISPR/Cas9 technology in neonatal NSCs of the subventricular zone blocks oligodendrocyte differentiation without affecting survival or proliferation of OPCs. We reproduced this differentiation defect in OPC differentiation cultures using an AAV9 vector to induce a CRISPR-mediated LOF of Tns3. We have generated a Tns3Flox mouse allele and are currently inducing OPC-specific LOF Tns3 in vivo and in vitro to confirm these results and explore the cellular phenotypes of the mutant OPCs. Using the Tns3 mouse line labelled V5, we will perform a proteomics to identify Tns3 partner proteins and understand the molecular mechanisms of Tns3 function in oligodendrocyte differentiation.
  • Pharmacogenomic identification of bioactive small molecules to promote oligodendrogenesis in a model of neonatal brain injury (RNA funded project 2017-2022).
    As part of our NeoRepair project, we have proposed and successfully achieved the following objectives: we have generated enriched expression gene sets in oligodendroglia, see Figure 1 (Step 3), through their expression in dorsal NSCs/NPCs that actively promote oligodendrogenesis at neonatal stages (1), and through their enriched expression in oligodendroglial cells, relative to other brain cell types (2). These oligodendroglial gene sets were then subjected to bioinformatic tools to identify their networks and transcriptional nuclei (4), and to pharmacogenomic analysis to identify the small bioactive molecules (drugs) that promote their expression (5). In view of the large number of results obtained by these approaches and in order to assess their impact on oligodendrogenesis, we have introduced a knowledge-based scoring procedure (6), based on functional studies demonstrating the requirement of a given gene in different aspects of oligodendrogenesis (specification, proliferation, migration, survival, differentiation, myelination and remyelination of OPC cells), by surveying over 2000 publications involving approximately 400 genes. Pharmacogenomic analysis of this selected set of genes identified 393 small molecules promoting different aspects of oligodendrogenesis (7), 221 of which also regulate our oligodendroglium-enriched gene sets. Our scoring procedure allowed us to classify small molecules according to the impact of their target genes in different oligodendrogenetic processes (8), and to select 40 new small molecules with putative pro-oligodendrogenic activity. Pharmacological analyses (pharmacokinetics and drug dynamics) allowed us to select 12 small molecules (9). Finally, we validated the pro-oligodendrogenic activity of these small molecules in differentiation cultures using neural progenitors (10) or primary OPCs (11), with most small molecules showing higher activity than positive controls currently in clinical trials, such as thyroid hormone (T3) normally used to promote OPC differentiation in culture, or clemastine, an antihistamine drug.
  • Molecular mechanisms of Ascl1 function in oligodendrogenesis versus neurogenesis
  • Evaluation of new FDA-approved drugs with in vitro validated oligodendrogenic activity in preclinical mouse models of multiple sclerosis (proposed funding to PMRA in 2021).
  • dThe chromatin remodelers CHD8 and Chd7 in the various genetic programs of oligodendrocyte progenitors and neural progenitors.

Team(s)

Team

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