Abstract：
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.
摘要：
真皮成纤维细胞在出生后失去干细胞效力，这阻碍了再生愈合。然而,潜在的细胞内机制在很大程度上是未知的。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头状成纤维细胞（PFs）的出生后成熟。随着H3K27ac水平的降低，出生后PF的再生能力丧失。单细胞转录组学，转座酶可接近的染色质测序测定法(ATAC-seq)，和染色质免疫沉淀测序（ChIP-seq）揭示了出生后成熟轨迹与PF中再生轨迹的丧失有关，其特征在于染色质可及性和H3K27ac修饰的显著降低。组蛋白去乙酰化酶抑制延迟自发染色质重塑，从而维持产后PFs的再生能力。基因组分析确定Twist2是染色质区域内的主要调节因子，在出生后期间可及性降低。当Twist2在真皮成纤维细胞中基因缺失时，出生后成熟的细胞内级联明显延迟。我们的发现揭示了真皮成纤维细胞出生后内在变化的综合细胞内机制。
