ReGenT-seq identifies a chromatin-to- cell protrusion mRNA transport for epidermal cell activation

In response to stress, cells exploit plasticity to self-activate and form protrusions to explore the surroundings and guide migration. While the initiation of protrusions is well-characterized, little is known about their maturation and functional composition. Here, using a new pooled genetic approach (ReGenT-seq) to screen all the chromatin factors controlling epidermal stem cell activation, we unexpectedly identified Cbx3 as a critical protrusion founder. Beyond its nuclear activities, we revealed a cytoplasmic moonlighting function of Cbx3, essential for governing the subcellular localization of specific mRNAs within polarizing protrusions of migrating epidermal stem cells but also in invadopodia of squamous carcinoma cells. This Cbx3-dependent mRNA transport promotes the localized establishment of several organelles including the Endoplasmic Reticulum and lysosomes in maturating protrusions, as well as focal adhesion dynamics. Thus, we uncovered a multilayered control of gene expression to regulate cell motility through protrusionogenesis, and in particular a chromatin-to-cellprotrusion mRNA transport that represents a potential therapeutic target to favor wound healing and contrast cancer invasion.