ZNF280B Mediates DPC-HFSC Crosstalk to Regulate Hair Follicle Stem Cell Fate

Wool fibre diameter is a key economic trait in wool-producing animals, and its formation is regulated by the synergistic interaction between the proliferation and differentiation of hair follicle stem cells (HFSCs) and signals from the microenvironment. Dermal papilla cells (DPCs), as a key signal source, regulate the fate of HFSCs via paracrine pathways; however, the key molecular mechanisms remain unclear. Single-cell RNA sequencing (scRNA-seq) and genome-wide association studies (GWAS) revealed that ZNF280B is specifically expressed in both DPCs and HFSCs, and its g.677G>A variant is significantly associated with wool fibre diameter. Functional studies indicate that overexpression of ZNF280B promotes the proliferation of DPCs and HFSCs and inhibits apoptosis, whilst knockdown has the opposite effect; mechanistically, ZNF280B alters mRNA levels of key marker genes of the Wnt/β-catenin signalling pathway while selectively changing transcripts of the TGF-β pathway components in DPCs, and differentially modulates key marker transcripts in both the Wnt/β-catenin and Notch pathways in HFSCs. In summary, ZNF280B mediates the paracrine signalling of DPCs to influence HFSC proliferation and differentiation. It achieves this by integrating the Wnt/β-catenin/TGF-β/Notch signalling axes. This reveals that ZNF280B acts as an important regulatory node mediating DPC-HFSC paracrine communication, and provides new insights into the developmental mechanisms of fine-wool hair follicles and molecular breeding for fibre diameter.