Guillaume Andrey

Epigenetic Control of Developmental Processes

Epigenetic Modulation of Gene Regulatory Landscapes

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During embryogenesis, the control of gene expression in time and in space allows for the normal morphogenesis of organs and structures. The molecular processes that orchestrate these genetic programs are thus essential for ontogenesis and their perturbations can lead to malformations or diseases. One of such processes is the communication, in the nuclear space, between gene regulatory regions and genes themselves. This communication is propagated through the 3D architecture of the genome, specifically through chromatin interactions, that can either be tissue-invariant or tissue-specific. In the latter case, the occurrences of interactions associate with the activities of genes. Yet, it remains unknown if these dynamics constitute a passive byproduct of gene activation or an active driver controlling the onset and offset of gene expression.

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So far, the most characterized role of the vertebrate chromatin organization is to structurally guide enhancer-promoter interactions into defined genomic intervals, termed Topologically Associating Domains (TADs), which possess a higher frequency of internal interaction. Within TADs, the regulatory architecture between enhancers and promoters can be either tissue-invariant or tissue-specific. In the latter case, the dynamics of interactions associate with the transcriptional activities of genes, yet the functions of these tissue-specific interactions and the underlying mechanisms controlling them remain largely uncharacterized. Most importantly, the causality of chromatin interactions in regulating genes in vivo remains largely uncharacterized. In the laboratory, we are studying the regulatory role that these dynamic chromatin interactions play in establishing the tightly regulated expression patterns of development genes, which ultimately control the morphogenesis of organs and structures, remains to be determined.

 

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Single Cell Transcriptomics of Complex Morphogenetic Processes

The transcriptional effect of mutations affecting complex developing tissues in human patients as well as in mouse models is so far assessed via bulk RNA quantification. Although this type of approach gives a quantitative idea of the transcriptional changes undergoing in the whole tissue, it lacks the cellular resolution necessary to understand where, when and how the mutation induces its pathogenic effect. Here, we use single cell RNA-seq (scRNA-seq) to profile the effect of re-engineered human structural variants using during mouse limb development. The goal of this study will be to determine the precise transcriptional changes taking place within limb cell populations from which these complex phenotypes arise and to establish scRNA-seq as a standard methodology to evaluate non-coding genetic alterations for ongoing and future works.