Twist2-driven chromatin remodeling governs the postnatal maturation of dermal fibroblasts

• Published in: Cell reports (Cambridge) 2022-05, Vol.39 (7), p.110821-110821, Article 110821
• Main Authors: Kim, Jin Yong, Park, Minji, Ohn, Jungyoon, Seong, Rho Hyun, Chung, Jin Ho, Kim, Kyu Han, Jo, Seong Jin, Kwon, Ohsang
• Format: Article
• Language: English
• Subjects: Chromatin; chromatin accessibility; Chromatin Assembly and Disassembly; Chromatin Immunoprecipitation Sequencing; CP: Developmental biology; CP: Molecular biology; dermal fibroblast; Fibroblasts; H3K27ac modifications; hair follicle; papillary fibroblast; postnatal maturation; Transposases - genetics; Twist2
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Postnatal papillary fibroblasts lose regenerative ability when H3K27ac levels decrease•Chromatin accessibility is decreased along with H3K27ac levels in postnatal fibroblasts•HDAC inhibition delays postnatal chromatin remodeling, which prevents WNT inactivation•Twist2 deletion in fibroblasts is sufficient to delay the postnatal maturation process Kim et al. show that postnatal papillary fibroblasts lose regenerative ability when H3K27ac levels decrease. Chromatin accessibility is decreased along with H3K27ac modifications. HDAC inhibition delays chromatin remodeling, which prevents postnatal WNT inactivation. Genetic deletion of Twist2 in fibroblasts is sufficient to delay the postnatal maturation process.