HISTONE ACETYLATION CHANGES AND ASTROCYTIC RESPONSE IN A CONTEXT OF BRAIN EDEMA

MONTEVERDE BM; VIDOS C; MANAVELA L; BRANCHI GLF; RAMOS A.J; VILLARREAL A

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC)

Astrocytes respond to brain injury through a process of reactive astrogliosisinvolving transcriptional, phenotypic, and functional changes.Astrocyte functional changes have a high impact on brain injuryoutcome; however, the epigenetic mechanisms regulating gene expression,such as histone modifications, remain obscure. We haveshown that astrocytes exposed to pro-inflammatory signals increasethe level of histone acetylation. However, to date, there is no availabledescription on early epigenetic changes in injury-affected astrocytes.We hypothesize that hypo-osmolar stress promoted by earlyedema has an impact on global histone modifications and astrocytefunction. In a model of brain cortical injury by pial disruption in adultmale Wistar rats, we addressed the levels of H3K9ac in astrocytenuclei at 1.5- and 3.5-hours post injury. We observed, using immunofluorescence,a higher proportion of astrocytes with lower levelsof H3K9ac at 3.5 hours when compared to non-injured hemisphere.Also, the injury promoted an increase in GFAP and AQP4 immunoreactivitynear the injury core. In vitro, we exposed primary cultureof astrocytes to hypotonic (20, 30 and 40% osm) culture medium topromote hypo-osmolar stress. We observed a decrease in the levelsof H3K9ac and H3K27ac after 1 and 3 hours which were restoredto control values 24h- after recovery in complete isotonic medium.Reduction in histone acetylation was prevented by treatment withhistone deacetylase inhibitor Trichostatin-A. Interestingly, astrocytesexposed to lipopolysaccharide showed impaired NFkB (p65 subunit)nuclear translocation. Our results show that an edema-like microenvironmentpromotes a global histone acetylation reduction in astrocytes.During the recovery in histone acetylation levels, chromatinmight be re-decorated but in a “reactive epigenome”. However,reduced NFkB activation might be indicative of impaired astrocyteresponse during early stages of injury in a context of hypoosmolarstress.