HISTONE MODIFICATIONS AND CHROMATIN REMODELING AS AN EPIGENETIC MECHANISM MODULATING ASTROGLIOSIS IN BRAIN ISCHEMIA

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

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

Sociedad Argentina de Investigación Clínica (SAIC)

Acute brain injuries such as stroke have great impact in developingcountries like Argentina. Commonly, patients suffer a worsening intheir pathological condition as a consequence of neuroinflammation,a cellular response in which astrocytes and microglia are majorplayers. Astrocytes respond to injury through a phenomenon knownas reactive astrogliosis showing functional and phenotypic changesthat are stable in time. We have recently shown that pro-inflammatorystimulus with lipopolysaccharide leads to increased levels ofacetylated histone 3 in astrocytes suggesting that chromatin remodelingevents might modulate reactive pro-inflammatory phenotype.In this work we aim to study possible changes in histone modificationsat early time points after brain ischemia since such eventsmay ?prime? astrocytes for acquisition of specific reactive pro-inflammatoryphenotype. We exposed Wistar male adult rats to aunilateral ischemic brain injury by cortical devascularization andanalyzed abundance of histone modifications in astrocytes usingfluorescence microscopy and labelling with specific antibodies todetect astrocytes (anti-GFAP) and acetylated histone 3 (anti-H3ac).We observed a significant decrease of acetylated histone 3 in theischemic ?core? region. A similar result was observed in immunoblotsfrom primary cultures of astrocytes exposed to oxygen andglucose deprivation. Contrarily, penumbral astrocytes surroundingthe ischemic core showed increased levels of histone 3 acetylation.Interestingly, broad histone deacetylase inhibition with valproic acid,immediately after onset of injury, promoted exacerbated astrogliosisand neuronal death at longer time points.Our results indicate that reactive astrocyte epigenetic changes afterbrain focal ischemia are regionally-dependent and that overridingthat fine tunned control with hyperacetylation by VPA increases neuroinflammationand expands neuronal death.Grants: UBACYT, FONCYT, ISN-CAEN, APBIOTECH