Epidermal Loss of PRMT5 Leads to the Emergence of an Atypical Basal Keratinocyte-Like Cell Population and Defective Epidermal Stratification.

Abstract

During skin development, ectoderm-derived cells undergo precisely coordinated proliferation, differentiation, and adhesion to yield stratified epidermis. Disruptions in these processes can result in congenital anomalies, including ectodermal dysplasia and harlequin ichthyosis. PRMT5-an enzyme responsible for methylating arginine residues in histones and other proteins-maintains progenitor status in germ and limb bud cells. Similarly, in vitro evidence suggests that PRMT5 prevents differentiation of basal keratinocytes, leading us to hypothesize that PRMT5 preserves the stem-cell phenotype of keratinocytes in vivo. To test this possibility, we generated conditional knockout mice lacking Prmt5 in early ectoderm (embryonic day 7.5), impacting the entire epidermis. Prmt5 conditional knockouts exhibited gross skin defects, compromised skin barrier function, and reduced postnatal viability. Histological analyses revealed significant defects in epidermal stratification, without alterations in apoptosis or proliferation. Single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin with high-throughput sequencing analysis identified an atypical population of basal keratinocyte-like cells in Prmt5 conditional knockouts that exhibited a senescence-like program, characterized by increased Cdkn1a (p21), elevated senescence-associated secretory phenotype molecules (Igfbp2), and decreased developmental transcription factor (Trp63) expression. Our findings suggest that PRMT5 prevents basal keratinocyte senescence by repressing Cdkn1a, shedding light on the epigenetic regulation of basal keratinocyte maintenance and senescence in congenital skin disorders.