Lo Piccolo L.Yeewa R.Noisagul P.Monteil A.Shotelersuk V.Jantrapirom S.Mahidol University2026-05-112026-05-112026-06-19Iscience Vol.29 No.6 (2026)https://repository.li.mahidol.ac.th/handle/123456789/116683YEATS2 is a chromatin-associated factor that regulates dopaminergic (DAergic) synaptic integrity, although its mechanism of action remains unclear. Here, we profiled head transcriptomic changes following neuron-specific YEATS2 knockdown in Drosophila. This analysis revealed coordinated downregulation of metabolic genes alongside upregulation of G protein-coupled receptor (GPCR) signaling components. YEATS2 loss led to elevated intracellular calcium, indicating calcium overload in the nervous system, and was associated with seizure-like activity, locomotor deficits, and loss of DAergic neurons, while sparing glutamatergic neurons and mushroom bodies. Genetic and pharmacological inhibition of store-operated calcium entry (SOCE) via the Orai channel, as well as blockade of ryanodine receptors, improved stress-induced phenotypes, restored calcium balance, and preserved DAergic neuron integrity. Together, these findings identify ER-centered calcium dysregulation as a key downstream consequence of YEATS2 loss and define a YEATS2-dependent epigenetic-calcium axis that links chromatin regulation to neuronal excitability and selective dopaminergic vulnerability.MultidisciplinaryArticleSCOPUS10.1016/j.isci.2026.1158552-s2.0-10503771360525890042