2. Academic Validation
  3. Antecedent enhancer activity predicts future susceptibility to seizures in mice

Antecedent enhancer activity predicts future susceptibility to seizures in mice

  • Nat Commun. 2026 Jan 8;17(1):300. doi: 10.1038/s41467-025-65346-2.
Benjamin D Boros # 1,  Mariam A Gachechiladze # 2 3,  Juanru Guo 2,  Dylan A Galloway 1,  Shayna M Mueller 2 3,  Mark Shabsovich 1,  Allen Yen 2 3,  Xuhua Chen 2,  Alexander J Cammack 1,  Tao Shen 1,  Robi D Mitra 4 5,  Joseph D Dougherty 6 7 8,  Timothy M Miller 9
Affiliations

Affiliations

  • 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • 4 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 5 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 6 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 7 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 8 Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 9 Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • # Contributed equally.
PMID: 41507153 DOI: 10.1038/s41467-025-65346-2
Abstract

Wide variation of responses to identical stimuli presented to genetically inbred mice suggests the hypothesis that stochastic non-genetic variation, such as in chromatin state or enhancer activity during neurodevelopment, can mediate such phenotypic differences. However, this hypothesis is largely untested since capturing pre-existing molecular states requires non-destructive, longitudinal recording. Therefore, we tested the potential of Calling Cards (CC) to record transient neuronal enhancer activity during postnatal development in mice, and thereby associate such non-genetic variation with a subsequent phenotypic presentation - degree of seizure response to the pro-convulsant pentylenetetrazol. We show that recorded differences in enhancer activity at 243 loci predict a severe vs. mild response, and that these are enriched near genes associated with human epilepsy. We also validated pharmacologically a seizure-modifying role for two previously unassociated genes, Htr1f and Let7c. This proof-of-principle supports using CC broadly to discover predisposition loci for Other neuropsychiatric traits and behaviors. Finally, as human disease is also influenced by non-genetic factors, similar epigenetic predispositions are possible in humans.

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