To Seize or Not to Seize? That is the (Epigenetic) Question

Antecedent Enhancer Activity Predicts Future Susceptibility to Seizures in Mice Boros BD, Gachechiladze MA, Guo J, Galloway DA, Mueller SM, Shabsovich M, Yen A, Chen X, Cammack AJ, Shen T, Mitra RD, Dougherty JD, Miller TM. Nat Commun . 2026, Jan 8;17(1):300. https://doi.org/10.1038/s41467-025-65346-2 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.