Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification.

Journal: Cell reports
Published Date: May 9, 2025

Abstract

Chromatin and DNA modifications mediate the transcriptional activity of lineage-specifying enhancers, but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly resolved timeline of their dynamics during neural progenitor cell differentiation. We discovered that, while complete demethylation appears delayed relative to shorter-lived chromatin changes for thousands of enhancers, DNA demethylation actually initiates with 5-hydroxymethylation before appreciable accessibility and transcription factor occupancy is observed. The extended timeline of DNA demethylation creates temporal discordance appearing as heterogeneity in enhancer regulatory states. Few regions ever gain methylation, and resulting enhancer hypomethylation persists long after chromatin activities have dissipated. We demonstrate that the temporal methylation status of CpGs (mC/hmC/C) predicts past, present, and future chromatin accessibility using machine learning models. Thus, chromatin and DNA methylation collaborate on different timescales to shape short- and long-term enhancer regulation during cell fate specification.

Authors

  • Lindsey N Guerin
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Timothy J Scott
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Jacqueline A Yap
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Annelie Johansson
    Biomodal, Chesterford Research Park, Cambridge CB10 1XL, UK.
  • Fabio Puddu
    Biomodal, Chesterford Research Park, Cambridge CB10 1XL, UK.
  • Tom Charlesworth
    Biomodal, Chesterford Research Park, Cambridge CB10 1XL, UK.
  • Yilin Yang
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Alan J Simmons
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Ken S Lau
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Rebecca A Ihrie
    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • Emily Hodges
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: emily.hodges@vanderbilt.edu.

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