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Understanding the retinoids-driven cell-fate gene regulatory programs during the in vitro reconstitution of the nervous system complexity

le 8 juin 2017
de 11h30 à 12h30

Séminaire de Marco Antonio Mendoza Parra (IGBMC, Strasbourg), candidat chef d'équipe

Studying living organisms as an ensemble of components in which the whole is the consequence of the complexity of their interactions represents the biggest challenge of the current “big-data omics” era. In fact, these days genomes sequencing is not only matter of revealing its digital nature (i.e. the nucleotides combinations defining the genetic code) but in addition it is used in combination with molecular biology techniques to interrogate functional protein genome interactions (ChIP-seq); the genome transcriptional activity (RNA-seq; GRO-seq); its chromatin accessibility (DNase-seq, FAIRE-seq, Mnase-seq) and more recently its three-dimensional organization (Hi-C, ChIA-PET). Importantly, the combination of each of these readouts will provide means to describe living systems through the reconstitution of their genomic-regulatory functions which are at the basis of their defined state. Moreover, understanding the reorganization of their regulatory wires – as a consequence of external/internal cues – represents a new approach to interpret the acquisition of novel physiological or aberrant system states. In a cellular context, the detailed comprehension of these reorganizations, known as cell fate transitions, is a major component of the novel therapeutic developments in regenerative medicine.

Cell fate transitions are at the basis of the genesis of multicellular organisms, and alterations from this body plan can generate pathologies. One such process is neurogenesis, a highly complex event implicating a variety of regulatory signals, which in a multicellular organization context (~ 80 billions of neurons interconnected by several trillions of interconnections) gives rise to one of the most complex organs retrieved in higher organisms: the brain.

From the developmental point of view, the capacity of a single trigger like the retinoic acid (RA) to induce neurogenesis in a variety of in vitro model systems, as well as its implication in the development of the nervous system in vivo, has been well documented over the years. Indeed our previous studies provided a comprehensive view of the RA-driven gene regulatory programs implicated in neuronal cell fate commitment (Mendoza-Parra et al; Genome Res 2016) and currently we are aiming at stratifying such gene regulatory wires in the context of the complexity of the various RAR/RXR heterodimers (composed by the various isotypes: RARalpha, RARbeta, RARgamma, RXRalpha, RXRbeta, RXRgamma); the initial mediators of the RA signaling. Indeed, previous studies demonstrated that each RAR/RXR combination could regulate different gene targets in different model systems, further supported by the capacity of defined RAR-specific agonists to mimic the differentiation phenotype induced by the pan-RAR/RXR activator, the all-trans Retinoic acid.

Finally, over the last years, several studies are providing evidence for a direct link between RA signaling in the adult brain and Alzheimer's disease (AD) or psychiatric disorders like schizophrenia. In fact RAR/RXR nuclear receptors are expressed in a variety of brain areas and their respective deletion, or a deficiency in retinoic acid supply in mouse model systems has been shown to lead to deficits in synaptic plasticity, learning, memory, as well as accumulation of amyloid ?; one of the two hallmarks of Alzheimer disease. For these reasons, a deep understanding of the RAR/RXR-derived gene regulatory programs in this process might help to elucidate the molecular mechanisms for their attributed neuroprotective properties, as well as to better orient the scientific community towards the development of retinoid drugs targeting for instance Alzheimer's disease.

In this context, my future studies will be focused on decorticating the complexity of the various RAR/RXR-derived gene regulatory networks implicated in neuronal cell fate commitment, nervous system homeostasis and their implication in degenerative diseases like Alzheimer. This will be performed by taken advantage of in-vitro cerebral organoid cultures, on which modern genetic approaches (CRISPR-Cas9 knockout; CRISPR-Cas9-mediated promoter activation) as well as spatio-temporal functional genomic readouts will be combined to reconstruct a systems biology view of nervous system complexity.  

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Amphi Serge Kampf
Mise à jour le 19 mai 2017

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