Lineage commitment of dermal fibroblast progenitors is controlled by Kdm6b-mediated chromatin demethylation.
Lineage commitment of dermal fibroblast progenitors is controlled by Kdm6b-mediated chromatin demethylation.
复制标题
DOI：
10.15252/embj.2023113880
复制
发表时间：
2023-10-04
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
真皮成纤维细胞前体细胞(DFP)在皮肤发育过程中分化为不同的成纤维细胞系。然而，调控DFP分化的表观遗传学机制尚不清楚。我们的目标是使用多模式单细胞方法、表观遗传学分析和同种异体移植技术来定义DFP状态和控制其分化潜力的机制。我们的初步结果表明，DFPS的总转录水平受到H3K27me3的抑制，并且在谱系特异的基因上有不可接近的染色质。令人惊讶的是，DFPS的抑制染色质特征使它们无法在同种异体移植试验中改造皮肤，尽管它们具有多潜能。我们推测染色质去抑制受H3K27me3去甲基酶KDM6B/Jmjd3的调节。小鼠皮肤成纤维细胞特异性KDM6B/Jmjd3的缺失导致脂肪细胞室消融和成熟毛乳头功能的抑制，额外的单细胞RNA-SEQ、CHIP-SEQ和同种异体移植试验证实了这一点。我们的结论是，在小鼠皮肤发育过程中，KDM6B/Jmjd3在功能上降低了DFPS的表达。因此，我们的研究揭示了对DFPS如何分化为不同的成纤维细胞谱系的多模式理解，并提供了一种新的公开可用的多组学搜索工具。真皮成纤维细胞前体细胞的分化需要KDM6B/Jmjd3去除抑制染色质标记才能使小鼠正常皮肤发育。
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. Differentiation of dermal fibroblast progenitors requires removal of repressive chromatin marks by Kdm6b/Jmjd3 for normal skin development in mice.
登录
查看更多内容
影响因子：
3.6
作者：
Driskell RR;Jahoda CA;Chuong CM;Watt FM;Horsley V
通讯作者：
Horsley V
影响因子：
23.9
作者：
Adam RC;Yang H;Ge Y;Lien WH;Wang P;Zhao Y;Polak L;Levorse J;Baksh SC;Zheng D;Fuchs E
通讯作者：
Fuchs E
DOI：
10.1007/978-1-62703-505-7_15
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Chen JS;Longaker MT;Gurtner GC
通讯作者：
Gurtner GC
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
64.5
作者：
Claudia Salzer, Marion;Lafzi, Atefeh;Aznar Benitah, Salvador
通讯作者：
Aznar Benitah, Salvador