The role of Ten Eleven Translocation enzymes in the hair follicle mesenchyme

Abstract

Epigenetic mechanisms play an important role during the morphogenesis of the hair follicle and the hair cycle. Work on hair regeneration is of importance as no products are available which can provide complete reversal of hair loss. Tet2 promotes DNA demethylation by the hydroxylation of 5mC to 5hmC which in turn causes gene transcription activation. Dermal papilla (DP) cells located within the hair follicle are responsible for the regulation of development and the growth of hair follicles. Fgf20 signalling controls commitment of the mesenchymal precursor cells to the DP progenitor lineage. An immature DP cells is then formed during maturation by Shh signalling which then stimulates these to differentiate into a DP cell by BMP and Wnt signalling. Methylated DNA can be bound by the proteins recruiting transcription corepressors. DNA methyltransferases (DNMT’s) can be degraded by decitabine which reverses gene silencing. Conditional knockout of Tet2 in mouse DP cells results in a delay in anagen initiation, suggesting Tet2 is involved in the telogen-anagen transition. Additionally, by using dermal fibroblasts and RA-DPAC (Dermal Papilla activating medium supplemented with retinoic acid), it was found that decitabine can increase plasticity in dermal fibroblasts and RA-DPAC can be used to accelerate a lineage change to DP cells which is supported by the significant increase in the DP specific gene expression. Examples include AlPl, LEF1, BMP4/6/7, FGF10, BMPR1A and PDGFA. Additionally, by way of siRNA and conditional Tet2 knockout data in dermal fibroblasts, it was found Tet2 regulates signature DP genes such as Bmpr1a, ALPL, Tcf4 and SOX2.