Cells are able to sense mechanical cues from their environment and respond by activating distinct genetic and biochemical signalling cascades that influence cell differentiation and function. This connection, which remains poorly explored, is likely to play a critical role during embryonic development and organ formation, as embryonic cells are highly dynamic in nature. They are constantly moving, undergoing profound changes in shape, and interacting with diverse environments that exert different mechanical forces upon them. However, we still do not understand how these forces are integrated at the genetic and molecular level, nor what type of cellular memory is used to faithfully propagate mechanical or geometrical changes over time.
The overarching goal of the laboratory is therefore to elucidate how external mechanical forces are translated into distinct cellular and nuclear conformational states, and consequently into gene regulatory signals, during early vertebrate embryonic development.
YAP is one of the best-characterised mechanosensitive proteins, acting as a sensor that transduces mechanical signals into biochemical processes and changes in the transcriptional state of the cell. Our objective is to use YAP as a reference indicator to identify additional mechanosensitive proteins, which together would constitute a cellular connectome responsible for transmitting environmental information to the cell. This approach will also enable us to investigate how nuclear geometry and substrate-derived mechanical forces impact the global epigenome, which we will define as a set of mechanosensitive gene regulatory regions (mGRRs). In parallel, we will identify changes in the cellular mechanosensing apparatus using high-resolution microscopy techniques and link these structural alterations to the differential usage of mGRRs under a range of mechanical perturbations.
We will subsequently exploit these mGRRs to study mechanosensitive processes during embryonic development, including the emergence of early “mechanical boundaries” and morphogenetic events known to depend on highly specific cellular geometries, such as collective cell migration or epiboly during gastrulation and optic cup formation. Finally, we will integrate all this information to compare development in vivo (embryos) and in vitro (organoids), and to determine the extent to which gene regulation—and in particular mechanosensitive regulation—is conserved in organoids. This will allow us to identify the biological substrates that most faithfully recapitulate the in vivo organism, not only at the morphological level, but also at the epigenetic level.
