DNA dioxygenases Tet2/3 regulate gene promoter accessibility and three-dimensional chromatin topology in lineage-specific loci to control hair growth

Lineage-specific and functionally-related genes frequently form conserved clusters or loci in the mammalian genomes. Execution of lineage-specific differentiation programs requires tight coordination between many regulators including Ten-eleven translocation (TET) family enzymes catalyzing DNA oxidation. However, the role of Tet genes in the control of cell differentiation at the levels of lineage-specific gene loci is unknown. Epithelial keratin genes are organized in the genome into two distinct (Keratin type I and II) loci on mouse chromosomes 11 and 15. Here, by using Keratin 14-driven ablation of Tet genes in skin epithelial cells, we demonstrate that Tet enzymes play essential roles in the control of gene expression in Keratin type I/II gene loci and execution of hair-specific differentiation program. Mice with Keratin 14-driven ablation of Tet2/Tet3 or all three Tet genes exhibit marked alterations of hair shape and length followed by hair loss. We show that through DNA demethylation, Tet2 and Tet3 control chromatin accessibility, Dlx3 binding and promoter activity of the Krt25 and Krt28 genes regulating hair shape, as well as regulate interactions between the Krt28 gene promoter and distal enhancer. However, Tet2/3 also control three-dimensional chromatin topology in Keratin type I/II gene loci via catalytic activity-independent mechanisms. These data demonstrate for the first time 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.