Histone chaperone Hira in melanoblast development and melanocyte stem cell ageing

Epigenetic mechanisms play an important role in development and ageing, and evidence exists that suboptimal in utero development can translate into epigenetic alterations and diseases later in childhood and with age. Hira is a histone chaperone that deposits H3.3 histone variant into the chromatin of non-dividing cells, but has also been shown to play a role in early development. Here, we describe a new conditional knockout mouse model, Tyr::Cre Hirafl/fl, in which melanocytes are specifically deficient for Hira. Early in embryonic development, Tyr::Cre Hirafl/fl embryos have fewer melanoblasts than wild type embryos, without any effect on migration or proliferation. However, by birth, Tyr::Cre Hirafl/fl mice contain a comparable number of melanocytes as wild type mice, albeit with less histone H3.3 and a very mildly hypopigmented first hair coat. Subsequently, their coat colour becomes progressively white with age, exacerbated by sequential depilations. This demonstrates a marked premature hair graying phenotype, linked to melanocyte stem cell depletion, suggesting a defect in stem cell maintenance. While constitutive Hira-deficient melanocytes from Tyr::Cre Hirafl/fl mice fail to grow in vitro, postnatal knockout of Hira does not show any marked phenotype. These data suggest a specific a role for Hira in the development of the melanocytic lineage, which generates an almost imperceptible phenotype at birth, but subsequently manifests as a premature aging phenotype.