Inactivation of Histone Chaperone HIRA Unmasks a Link Between Normal Embryonic Development of Melanoblasts and Maintenance of Adult Melanocyte Stem Cells

Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage-specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest-derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single-cell RNA sequencing analysis indicating evidence of lineage-specificity defects. This was supported in an in vitro model using melb-a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC-seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere-associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue-specific stem cells during aging.