Chromatin remodeling as an underlying epigenetic mechanism of astrocyte neuroinflammatory phenotype stability

VILLARREAL ALEJANDRO; VIDOS C; MONTEVERDE BUSSO, MATÍAS; CIERI MB; RAMOS AJ

Congreso; Sociedad Argentina de Neurociencias Reunión Anual 2021; 2021

Sociedad Argentina de Neurociencias (SAN)

Astrocytes respond to brain injury through a phenomenon called ?reactive astrogliosis?, in which a pro-inflammatory and pathological phenotype has been described, thus representing a promising target to reduce damage propagation after injury.Astrocyte pro-inflammatory gain of function involves stable transcriptomic changes probably following transcription factor NF-kB activation. We hypothesized that astrocyte pro-inflammatory phenotype is sustained by NF-kB-associated epigenetic mechanisms that regulate gene expression.Using mouse primary glial cultures we observed that the pro-inflammatory stimulus LPS (Lipopolysaccharide) promotes NF-kB activation first in microglia and then in astrocytes where it remained active for 72hs. The strength of initial activation in astrocytes depended on microglia abundance and the release of microglial soluble factors.We further observed a microglial-dependent increase in gene activating histone marks H3K9K14ac and H3K27ac and a decrease in the repressive mark H3K9me3. In vivo, H3K27ac increased specifically in reactive astrocytes in a model of brain ischemia by cortical devascularization in rats.The observed changes in histone modification abundance dynamically occurred in pro-inflammatory astrocytes suggesting events of chromatin remodeling. Such mechanisms may represent plausible targets to reduce astrocyte pro-inflammatory phenotype, neuroinflammation and neuronal loss after brain injury.Grants: UBACYT, FONCYT, ISN-CAEN, APBIOTECH