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

Development. 2020 Mar 12;147(5):dev182576. doi: 10.1242/dev.182576.


In the neural crest lineage, progressive fate restriction and stem cell assignment are crucial for both development and regeneration. Whereas fate commitment events have distinct transcriptional footprints, fate biasing is often transitory and metastable, and is thought to be moulded by epigenetic programmes. Therefore, the molecular basis of specification is difficult to define. In this study, we established a role for a histone variant, H2a.z.2, in specification of the melanocyte lineage from multipotent neural crest cells. H2a.z.2 silencing reduces the number of melanocyte precursors in developing zebrafish embryos and from mouse embryonic stem cells in vitro We demonstrate that this histone variant occupies nucleosomes in the promoter of the key melanocyte determinant mitf, 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 the role of a histone variant upstream of the core gene regulatory network in the neural crest lineage. This epigenetic mark is a key determinant of cell fate and facilitates gene activation by external instructive signals, thereby establishing melanocyte fate identity.

Keywords: Epigenetic regulation; Fate-bias; Gene regulatory network; Histone variant; Melanocyte; Pigmentation; Specification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems / genetics
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Lineage
  • Embryonic Stem Cells / cytology*
  • Gene Regulatory Networks / genetics
  • Histones / genetics*
  • Melanocytes / cytology*
  • Melanoma, Experimental
  • Mice
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Neural Crest / cytology*
  • Zebrafish / embryology
  • Zebrafish Proteins / genetics*


  • H2az2 protein, mouse
  • Histones
  • Microphthalmia-Associated Transcription Factor
  • Mitf protein, mouse
  • Zebrafish Proteins
  • mitfa protein, zebrafish