H3K9me3 Methyltransferase SETDB1 Controls Retrotransposon Silencing, DNA Methylation, Constitutive Heterochromatin Maintenance and 3D-Chromatin Structure in Epidermal Keratinocytes
H3K9me3 SETDB1 epidermal keratinocytes heterochromatin transposable elements endogenous retroviruses DNA hypomethylation chromatin states double-stranded RNAs interferon-mediated immune response skin inflammation hair loss differentially methylated regions DNA accessibility RNA sequencing antiviral response pathways reverse transcriptase inhibitors T cell infiltration epidermal homeostasis inflammatory skin conditions ERVs DMRs RT inhibitors
TLDR SETDB1 is essential for controlling DNA methylation, silencing retrotransposons, and maintaining skin cell health, with its absence leading to skin inflammation and hair loss.
The study investigates the role of the H3K9me3 methyltransferase SETDB1 in epidermal keratinocytes (KCs), focusing on its impact on retrotransposon silencing, DNA methylation, heterochromatin maintenance, and 3D-chromatin structure. Conditional ablation of Setdb1 in KCs led to significant changes in epidermal differentiation, skin inflammation, and progressive hair loss. SETDB1-deficient KCs exhibited DNA hypomethylation, altered chromatin states, and increased expression of ERV-specific dsRNAs, triggering an interferon-mediated immune response. RNA-seq analysis revealed upregulation of antiviral pathways. Treatment with Tenofovir and Emtricitabine reduced T cell skin infiltration in Setdb1CKO animals. The findings highlight SETDB1's crucial role in maintaining epidermal homeostasis and controlling inflammatory skin conditions.
