School of Molecular Biosciences, Washington State University, Pullman, WA, USA.
North Rhine-Westphalia Technical University of Aachen, Aachen, Germany.
EMBO J. 2023 Oct 4;42(19):e113880. doi: 10.15252/embj.2023113880. Epub 2023 Aug 21.
Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the epigenetic mechanisms that regulate DFP differentiation are not known. Our objective was to use multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanism that governs its differentiation potential. Our initial results indicated that the overall transcription profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage-specific genes. Surprisingly, the repressive chromatin profile of DFPs renders them unable to reform the skin in allograft assays despite their multipotent potential. We hypothesized that chromatin derepression was modulated by the H3K27me3 demethylase, Kdm6b/Jmjd3. Dermal fibroblast-specific deletion of Kdm6b/Jmjd3 in mice resulted in adipocyte compartment ablation and inhibition of mature dermal papilla functions, confirmed by additional single-cell RNA-seq, ChIP-seq, and allografting assays. We conclude that DFPs are functionally derepressed during murine skin development by Kdm6b/Jmjd3. Our studies therefore reveal a multimodal understanding of how DFPs differentiate into distinct fibroblast lineages and provide a novel publicly available multiomics search tool.
真皮成纤维细胞祖细胞 (DFPs) 在皮肤发育过程中分化为不同的成纤维细胞谱系。然而，调控 DFP 分化的表观遗传机制尚不清楚。我们的目标是使用多模态单细胞方法、表观遗传检测和同种异体移植技术来定义 DFP 状态及其分化潜能的调控机制。我们的初步结果表明，DFPs 的整体转录谱受到 H3K27me3 的抑制，并且在谱系特异性基因处存在不可接近的染色质。令人惊讶的是，DFPs 的抑制性染色质图谱使它们无法在同种异体移植实验中重新形成皮肤，尽管它们具有多能性。我们假设染色质去抑制受 H3K27me3 去甲基酶 Kdm6b/Jmjd3 调节。在小鼠中，特异性敲除真皮成纤维细胞中的 Kdm6b/Jmjd3 导致脂肪细胞隔室消融和成熟真皮乳头功能抑制，这通过额外的单细胞 RNA-seq、ChIP-seq 和同种异体移植实验得到证实。我们得出结论，在小鼠皮肤发育过程中，DFPs 通过 Kdm6b/Jmjd3 被功能性去抑制。因此，我们的研究揭示了一种多模式的理解，即 DFP 如何分化为不同的成纤维细胞谱系，并提供了一种新的公开可用的多组学搜索工具。
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