ZFIN ID: ZDB-PUB-200227-2
Histone variant dictates fate biasing of neural crest cells to melanocyte lineage
Raja, D.A., Subramaniam, Y., Aggarwal, A., Gotherwal, V., Babu, A., Tanwar, J., Motiani, R.K., Sivasubbu, S., Gokhale, R.S., Natarajan, V.T.
Date: 2020
Source: Development (Cambridge, England)   147(5): (Journal)
Registered Authors: Sivasubbu, Sridhar
Keywords: Epigenetic regulation, Fate-bias, Gene regulatory network, Histone variant, Melanocyte, Pigmentation, Specification
Microarrays: GEO:GSE133141
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*
PubMed: 32098766 Full text @ Development
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 H2a.z.2 in specification of melanocyte lineage from multipotent neural crest cells. Silencing of H2a.z.2 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 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 to 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.