Abstract
Epidermal lineages and injury induced regeneration are controlled by transcriptional programs coordinating cellular signaling and epigenetic regulators, but the mechanism remains unclear. Previous studies showed that conditional deletion of the transcriptional coactivator Mediator 1 (Med1) changes epidermal lineages and accelerates wound re-epithelialization. Here, we studied a molecular mechanism by which Med1 facilitates these processes, in particular, by focusing on TGFβ signaling through genome wide transcriptome analysis. The expression of the TGF ligands (Tgfβ1/β2) and their downstream target genes is decreased in both normal and wounded Med1 null skin. Med1 silencing in cultured keratinocytes likewise reduces the expression of the ligands (TGFβ1/β2) and diminishes activity of TGFβ signaling as shown by decreased p-Smad2/3. Silencing Med1 increases keratinocyte proliferation and migration in vitro. Epigenetic studies using chromatin immuno-precipitation and next generation DNA sequencing reveals that Med1 regulates transcription of TGFβ components by forming large clusters of enhancers called super-enhancers at the regulatory regions of the TGFβ ligand and SMAD3 genes. These results demonstrate that Med1 is required for the maintenance of the TGFβ signaling pathway. Finally, we show that pharmacological inhibition of TGFβ signaling enhances epidermal lineages and accelerates wound re-epithelialization in skin similar to that seen in the Med1 null mice, providing new insights into epidermal regeneration.
Highlights
Skin epithelia are highly regenerative tissues developmentally derived from the ectoderm
We focused on the transforming growth factor β (TGFβ) signaling because our current genome wide transcriptomic studies presented in this report indicate that TGFβ is a top candidate for mediating Mediator 1 (Med1) action
Epidermis was separated from dermis in Med1 KO and CON mice at 10 wk of age when abnormal anagen shift was obvious in Med1 KO skin compared to CON skin
Summary
Skin epithelia are highly regenerative tissues developmentally derived from the ectoderm. They are differentiated into three appendages, interfollicular epidermis (IFE), sebaceous glands (SG) and hair follicles (HF). They drive lineage specific transcriptional programs potentially by coordinating cell signals and epigenetic regulators. Med regulates TGFβ signaling in epidermis whole skin (10 wk), and KO skin wounds (1d after wounding) are available with accession numbers GSE50672, GSE50671, GSE50670, respectively under the super-series GSE50673. The ChIP-seq data for keratinocytes immunoprecipitated with H3K27ac, CTCF and Med antibodies are available with accession number GSE154221
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