DNA dioxygenases Tet2/3 regulate gene promoter accessibility and chromatin topology in lineage-specific loci to control epithelial differentiation.

Execution of lineage-specific differentiation programs requires tight coordination between many regulators including Ten-eleven translocation (TET) family enzymes, catalyzing 5-methylcytosine oxidation in DNA. Here, by using --driven ablation of genes in skin epithelial cells, we demonstrate that ablation of results in marked alterations of hair shape and length followed by hair loss. We show that, through DNA demethylation, control chromatin accessibility and Dlx3 binding and promoter activity of the and genes regulating hair shape, as well as regulate interactions between the gene promoter and distal enhancer. Moreover, also control three-dimensional chromatin topology in Keratin type I/II gene loci via DNA methylation-independent mechanisms. These data demonstrate the essential roles for Tet2/3 in establishment of lineage-specific gene expression program and control of Dlx3/Krt25/Krt28 axis in hair follicle epithelial cells and implicate modulation of DNA methylation as a novel approach for hair growth control.