- Reaction score
- 950
Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression
Authors: Rene C. Adam4,6, Hanseul Yang6, Yejing Ge, Wen-Hui Lien5, Ping Wang, Yilin Zhao, Lisa Polak, John Levorse, Sanjeethan C. Baksh, Deyou Zheng, Elaine Fuchs7
Highlights
•Signal effectors and transcription factors collaborate in HF lineage progression
•Spatiotemporal signals converge on chromatin to elicit dynamic HF lineage changes
•Switching from WNT effectors TCF3/TCF4 to LEF1 drives stem cell lineage progression
•Lineage restriction occurs through WNT/LEF1 cooperation with BMP versus NOTCH pathways
Summary
Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by the microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of stem cell lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatiotemporal cues to chromatin dynamics, thereby choreographing stem cell 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, enhancers driving HF-stem cell master regulators are silenced. Concomitantly, multipotent, lineage-fated enhancers silent in HF-stem cells become activated by exchanging WNT effectors TCF3/4 for LEF1. Throughout regeneration, lineage enhancers continue reliance upon LEF1 but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity increase when diverse, signal-sensitive transcription factors shape LEF1-regulated enhancer dynamics.
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