Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul 03080, Korea; Department of Dermatology, Columbia University, New York 10032, NY, USA.
Department of Dermatology, Seoul National University College of Medicine, Seoul 03080, Korea; Laboratory of Cutaneous Aging and Hair Research, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul 03080, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
Cell Rep. 2022 May 17;39(7):110821. doi: 10.1016/j.celrep.2022.110821.
Dermal fibroblasts lose stem cell potency after birth, which prevents regenerative healing. However, the underlying intracellular mechanisms are largely unknown. We uncover the postnatal maturation of papillary fibroblasts (PFs) driven by the extensive Twist2-mediated remodeling of chromatin accessibility. A loss of the regenerative ability of postnatal PFs occurs with decreased H3K27ac levels. Single-cell transcriptomics, assay for transposase-accessible chromatin sequencing (ATAC-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) reveal the postnatal maturation trajectory associated with the loss of the regenerative trajectory in PFs, which is characterized by a marked decrease in chromatin accessibility and H3K27ac modifications. Histone deacetylase inhibition delays spontaneous chromatin remodeling, thus maintaining the regenerative ability of postnatal PFs. Genomic analysis identifies Twist2 as a major regulator within chromatin regions with decreased accessibility during the postnatal period. When Twist2 is genetically deleted in dermal fibroblasts, the intracellular cascade of postnatal maturation is significantly delayed. Our findings reveal the comprehensive intracellular mechanisms underlying intrinsic postnatal changes in dermal fibroblasts.
真皮成纤维细胞在出生后失去干细胞潜能，从而阻止了再生性愈合。然而，其内在的细胞内机制在很大程度上仍是未知的。我们揭示了由广泛的 Twist2 介导的染色质可及性重塑驱动的乳突成纤维细胞（PFs）的出生后成熟。随着 H3K27ac 水平的降低，出生后 PFs 的再生能力丧失。单细胞转录组学、转座酶可及染色质测序（ATAC-seq）和染色质免疫沉淀测序（ChIP-seq）揭示了与 PFs 再生轨迹丧失相关的出生后成熟轨迹，其特征是染色质可及性和 H3K27ac 修饰明显降低。组蛋白去乙酰化酶抑制延迟了自发的染色质重塑，从而维持了出生后 PFs 的再生能力。基因组分析鉴定出 Twist2 是出生后时期染色质可及性降低区域内的主要调节因子。当真皮成纤维细胞中的 Twist2 被基因删除时，出生后成熟的细胞内级联反应会显著延迟。我们的研究结果揭示了真皮成纤维细胞内在的出生后变化的全面细胞内机制。
