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
Keratin 14
–
Cre
–driven ablation of
Tet
genes in skin epithelial cells, we demonstrate that ablation of
Tet2/Tet3
results in marked alterations of hair shape and length followed by hair loss. We show that, through DNA demethylation,
Tet2/Tet3
control chromatin accessibility and 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. Moreover,
Tet2/Tet3
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.
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