SWI/SNF and PRC2-dependent epigenetic programs governing tissue outcome after brain ischemia

Ischemic stroke remains a leading cause of death and disability, yet the molecular mechanisms that determine whether peri-infarct tissue survives or progresses to irreversible damage are still poorly understood. Neurons and astrocytes in the ischemic penumbra undergo profound chromatin and stress -induced transcriptional changes in response to metabolic failure, excitotoxicity, inflammation and immune activation. Two major chromatin-remodeling systems SWItch/Sucrose Non-Fermentable (SWI/SNF, also known as BAF) complexes and the Polycomb Repressive Complex 2 (PRC2)are central regulators of gene expression, stress responses and fate decisions in both neuronal and glial populations. However, despite their established roles in neural development, synaptic activity and neuroinflammation, their contribution to ischemic brain injury remains largely unexplored. This project will dissect how SWI/SNF and PRC2 complexes regulate neuronal vulnerability, astrocyte reactivity and neuroinflammatory dynamics after cerebral ischemia. Our preliminary data show that neural injury triggers coordinated chromatin remodeling: neurons undergo selective shifts in SWI/SNF subunit composition that increase their vulnerability to metabolic stress, while astrocytes display injury-induced reorganization of PRC2 submodules. These findings suggest that early chromatin changes help shape injury trajectories. Using complementary in vitro and in vivo models, we will define how neuronal SWI/SNF and astrocytic PRC2 perturbations influence stress responses, survival pathways and neuroinflammation. We will also investigate how chromatin-dependent signals contribute to the recruitment and activation of skull bone marrowderived myeloid cells, a recently discovered inflammatory route with rapid impact on stroke pathology. By elucidating how chromatin remodeling modulates neuronastrocyteimmune communication after injury, this project aims to identify SWI/SNF- and PRC2-dependent pathways that enhance neuroprotection or limit inflammation, thereby revealing new strategies to preserve brain tissue and improve recovery after stroke. This work addresses an urgent clinical need and may establish key principles for epigenetic intervention in ischemic injury.