Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression

Rene C. Adam, Hanseul Yang, Yejing Ge, Wen Hui Lien, Ping Wang, Yilin Zhao, Lisa Polak, John Levorse, Sanjeethan C. Baksh, Deyou Zheng, Elaine Fuchs

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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. How external signals interface with chromatin to coax stem cells along distinct tissue lineage programs remains a mystery. Here, Adam et al. combine epigenomic, genetic, single-cell transcriptome, and chromatin sensor data to show how new fates are acquired through temporal layering of signaling effectors atop established chromatin platforms.

Original languageEnglish (US)
JournalCell Stem Cell
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Chromatin Assembly and Disassembly
Hair Follicle
Cell Lineage
Stem Cells
Chromatin
Regeneration
Epigenomics
Transcription Factors
Transcriptome
Mutagenesis
Cues
Drive

Keywords

  • Adult tissue regeneration
  • Chromatin remodeling
  • Epicenter
  • Hair follicle
  • Multipotent progenitors
  • Signaling effectors
  • Stem cell lineage choices
  • Super-enhancer
  • Transient amplifying cells
  • WNT signaling

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression. / Adam, Rene C.; Yang, Hanseul; Ge, Yejing; Lien, Wen Hui; Wang, Ping; Zhao, Yilin; Polak, Lisa; Levorse, John; Baksh, Sanjeethan C.; Zheng, Deyou; Fuchs, Elaine.

In: Cell Stem Cell, 01.01.2018.

Research output: Contribution to journalArticle

Adam, Rene C. ; Yang, Hanseul ; Ge, Yejing ; Lien, Wen Hui ; Wang, Ping ; Zhao, Yilin ; Polak, Lisa ; Levorse, John ; Baksh, Sanjeethan C. ; Zheng, Deyou ; Fuchs, Elaine. / Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression. In: Cell Stem Cell. 2018.
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