Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression [ATAC-seq]

Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of SC lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatio-temporal cues to chromatin dynamics, thereby choreographing SC lineages. Using enhancer-driven reporters, mutagenesis and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP-effector pSMAD1 is relieved, super-enhancers driving HF-SC master regulators become silenced. Concomitantly, multipotent, lineage-fated super-enhancers silent in HF-SCs become activated by exchanging WNT-effectors TCF3/4 for LEF1. Throughout regeneration, lineage super-enhancers continue reliance upon LEF1, but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity mount as diverse, signal-sensitive transcription factors shape LEF1-regulated super-enhancer dynamics.