EPIGENETIC MECHANISMS UNDERLYING ASTROGLIAL HETEROGENEITY IN REACTIVE ASTROGLIOSIS: TARGETING CHROMATIN REMODELERS AS A POSSIBLE THERAPY TO REDUCE DAMAGE AFTER BRAIN INJURY

VILLARREAL A

Congreso; Reunión anual de sociedades de biociencias 2021. Sociedad Argentina de Investigaciones Clínicas; 2021

Sociedad Argentina de Investigación Clínica (SAIC)

Astrocytes respond to brain injury through a phenomenon called reactiveastrogliosis in which a pro-inflammatory and pathological subpopulationof astrocyte has been described, capable of promotingneuroinflammation and neuronal death. Astrocyte pathological conversionwith a pro-inflammatory gain of function involves dramaticand stable transcriptomic changes, probably following activation oftranscription factor NF-kB. NF-kB interacts with chromatin remodellingenzymes and recruits them to regulatory regions of target genespromoting epigenetic changes in other cell types.We aim to address the epigenetic mechanisms that are associatedwith NF-kB activation in reactive astrocytes that might lead to theestablishment of an astrocyte pathological identity.Using immunofluorescence microscopy and PCR analysis in primarycultures of mouse cortical astrocytes with different microgliaabundance and exposed to pro-inflammatory stimulus LPS (Lipopolysaccharide),we observed that LPS significantly promoted: 1)Sequential NF-kB activation in microglia>>astrocytes together withmorphological and transcriptional changes, 2) A variable intensity ofinitial NF-kB activation in astrocytes depending on microglial abundanceand the release of microglial soluble factors and 3) A microglial-dependent increase in gene activating histone marks H3K9K14acand H3K27ac and a decrease in the repressive mark H3K9me3. Invivo brain ischemia recapitulated the increase in H3K27ac specificallyin reactive astrocytes from ischemic penumbra and inhibition ofhistone deacetylases exacerbated astrogliosis and brain damage.Our results showing changes in histone mark abundance are highlyindicative of chromatin remodeling events in a subpopulation ofpro-inflammatory reactive astrocytes. Such epigenetic mechanismsmay represent plausible therapeutic targets to reduce astrocytepro-inflammatory phenotype, neuroinflammation and neuronal lossafter brain injury.Grants: UBACYT, FONCYT, ISN-CAEN, APBIOTECH