Inactivation of histone chaperone HIRA unmasks a link between normal embryonic development of melanoblasts and maintenance of adult melanocyte stem cells (RNA-Seq)

Evidence indicates that the integrity of in utero embryonic development can influence late life healthy or unhealthy aging. However, specific links between embryonic development and late life aging are not well defined. Histone chaperone HIRA is thought to play a role in both early development and aging. Here, we explore the relationship between HIRA's roles in development and aging by comparing lineage-specific constitutive and conditional Hira knock out in the murine pigmentary system, with constitutive knock out initiated during embryogenesis and conditional knock out in young adults. Embryonic Hira knockout leads to reduced melanoblast numbers during embryogenesis but wild type numbers of differentiated melanocytes at birth, normally functioning juvenile and young adult melanocyte stem cells (McSCs), and only a very mildly hypopigmented first hair coat. However, on closer analysis of these mice, Hira knockout melanocytic cells of newborn mice exhibit molecular markers characteristic of cell aging and proliferative deficits. As they age, mice with Hira knock out initiated during embryogenesis display marked defects in McSC maintenance and premature hair graying. Importantly, these defects are only observed when HIRA is inactivated during embryogenesis, but not in young adults. This genetic model shows that HIRA function during early development lays a foundation for subsequent maintenance of adult tissue specific stem cells during aging. Overall design: RNA sequencing was used to study the transcriptomic changes of HIRA KD on in-vitro melb-a cells. We used parental non-transduced cells, two control lenti- shRNAs (shLuciferase, shScramble), as well as two lenti- shRNAs to knock down HIRA (shHIRA I, shHIRA II). Gene expression analysis was performed using data obtained from bulk-RNA seq of 20 samples (4 independent replicates per experimental group).