ABSTRACT

Expansion of epigenetically-regulated epidermal stem cell niches potentially accounts for the characteristic histopathology of psoriasis (Ps), a proliferative condition likened to defective wound healing and cancer. Previous work by us and others has emphasized the importance of ten-eleven translocation (TET) methylcytosine dioxygenase and resultant DNA hydroxymethylation by 5-hydroxymethylcytosine (5-hmC) in stem cell contributions to skin repair and oncogenesis, and we therefore posited a possible role for the TET/5-hmC epigenetic pathway in Ps. Human Ps and imiquimod-induced murine Ps both showed multiplex biomarker profiles characterized by 1) loss of 5-hmC in basal and suprabasal cells; and 2) activation and loss of cytokeratin 15-positive basal stem cells with attendant dramatic increase in suprabasal nestin- and fatty acid binding protein 5 (FABP5)-expressing transit amplifying cells (TACs).  This profile was specific to Ps and was confirmed by qRT-PCR. Loci-specific loss of 5-hmC was demonstrated by genome-wide mapping, identifying differentially hydroxymethylated genes involved in pathways integral to stem cell homeostasis and activation (e.g. retinoic acid receptor [RAR] activation, Wnt/-catenin and NOTCH1 signaling). In vitro, human KSCs undergoing dedifferentiation due to low [Ca++] lost 5-hmC and acquired a TAC phenotype that was reversed upon addition of the known TET/5-hmC modulator, ascorbic acid. Moreover, KSC dedifferentiation increased KSC IL-17R expression known to drive the psoriatic phenotype. These data for the first time establish keratinocyte stem cell activation as an early event in the genesis of the psoriatic epidermis, and implicate aberrant epigenomic expression of the TET/5-hmC pathway as a potentially reversible initiator of anomalous stem cell proliferation.