Epigenetic insights into GABAergic development in Dravet Syndrome iPSC and therapeutic implications

作者：Jens Schuster, Xi Lu, Yonglong Dang, Joakim Klar, Amelie S. Wenz, Niklas Dahl, Xingqi Chen · 发表于：eLife · 年份：2023 · DOI：10.7554/elife.92599.1 · 被引用次数：2 · 研究领域：Genetics and Neurodevelopmental Disorders、Epigenetics and DNA Methylation、Genomic variations and chromosomal abnormalities

Abstract Dravet syndrome (DS) is a devastating early onset refractory epilepsy syndrome caused by variants in the SCN1A gene. A disturbed GABAergic interneuron function is implicated in the progression to DS but the underlying developmental and pathophysiological mechanisms remain elusive, in particularly at the chromatin level. In this study, we utilized induced pluripotent stem cells (iPSCs) derived from DS cases and healthy donors to model disease-associated epigenetic abnormalities of GABAergic development. Employing the ATAC-Seq technique, we assessed chromatin accessibility at multiple time points (Day 0, Day 19, Day 35, and Day 65) of GABAergic differentiation. Additionally, we elucidated the effects of the commonly used anti-seizure drug valproic acid (VPA) on chromatin accessibility in GABAergic cells. The distinct dynamics in chromatin profile of DS iPSC predicted accelerated early GABAergic development, evident at D19, and diverged further from the pattern in control iPSC with continued differentiation, indicating a disrupted GABAergic maturation. Exposure to VPA at D65 reshaped the chromatin landscape at a variable extent in different iPSC-lines and rescued the observed dysfunctional development in some DS iPSC-GABA. This study provides the first comprehensive investigation on the chromatin landscape of GABAergic differentiation in DS-patient iPSC, offering valuable insights into the epigenetic dysregulations associated with interneuronal dysfunction in DS. Moreov...