Histone code dictates fate biasing of neural crest cells to melanocyte lineage

In the neural crest lineage, progressive fate-restriction and stem cell assignment are critical for both development and regeneration. While the fate-commitment events have distinct transcriptional footprints, fate-biasing is often transitory and metastable, and is thought to be moulded by epigenetic programs. Hence molecular basis of specification is difficult to define. In this study, we establish a role of a histone variant in specification of melanocyte lineage from multipotent neural crest cells. Silencing of reduces the number of melanocyte precursors in developing zebrafish embryos, and from mouse embryonic stem cells . We demonstrate that this histone variant occupies nucleosomes in the promoter of key melanocyte determinant , and enhances its induction. CRISPR-Cas9 based targeted mutagenesis of this gene in zebrafish drastically reduces adult melanocytes, as well as their regeneration. Thereby our study establishes a histone based specification code upstream to the core gene regulatory network in the neural crest lineage of melanocytes. This epigenetic code renders a poised state to the promoter of key determinant and enhances activation by external instructive signals thereby establishing melanocyte fate identity.