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

Abstract

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 <i>Keratin 14</i>-<i>Cre</i>-driven ablation of <i>Tet</i> genes in skin epithelial cells, we demonstrate that ablation of <i>Tet2/Tet3</i> results in marked alterations of hair shape and length followed by hair loss. We show that, through DNA demethylation, <i>Tet2/Tet3</i> control chromatin accessibility and Dlx3 binding and promoter activity of the <i>Krt25</i> and <i>Krt28</i> genes regulating hair shape, as well as regulate interactions between the <i>Krt28</i> gene promoter and distal enhancer. Moreover, <i>Tet2/Tet3</i> 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.