Mechanical control of histone serotonylation initiates neural crest migration in vivo

Collective cell migration (CCM) is pivotal in several biological contexts, and posttranslational modifications of histones are essential to initiate this process^1-3. Here, we show that a recently discovered chromatin mark, termed histone serotonylation⁴, is involved in the collective migration of cranial neural crest cells - an embryonic multipotent stem cell population⁵. Our in vivo data reveal that histone serotonylation appears in neural crest cells just before they start migrating and that its occurrence is essential to initiate their CCM. Surprisingly, we found that stiffening of the neural crest migratory substrate, the mesoderm, induces histone serotonylation by promoting nuclear translocation of transglutaminase 2 (Tgm2), the enzyme responsible for adding serotonin to histones⁴. Moreover, mechanical and molecular perturbations demonstrate that mechanical shuttling of Tgm2 into the nucleus, with concomitant increases in histone serotonylation, are both required and sufficient to allow CCM in vivo. Furthermore, integrated chromatin immunoprecipitation and RNA sequencing analyses uncover a transcriptional module, which is enabled by histone serotonylation in response to mesoderm stiffening. Altogether, our results provide in vivo evidence showing that tissue stiffening leads to increased levels of histone serotonylation to reinforce permissive patterns of gene expression, supporting the switch from non-migratory to migratory cell states.