Epigenetic regulation of gpm6a after prenatal stress

MONTELEONE, MELISA C; ADROVER, EZEQUIELA; PALLARÉS, MARÍA EUGENIA; ANTONELLI, MARTA C; ALBERTO C. FRASCH; BROCCO MA

Braga

Workshop; Epigenetic plasticity: Implications in neural (dys)function; 2014

EMBO

Epigenetic regulation of gpm6a after prenatal stress Melisa C. Monteleone1, Ezequiela Adrover2, María Eugenia Pallarés2, Marta C.Antonelli2, Alberto C. Frasch1 and Marcela A. Brocco1 1 Instituto de Investigaciones Biotecnológicas (IIB)-INTECH-UNSAM-CONICET, Buenos Aires, Argentina; 2 IQUIFIB, Universidad de Buenos Aires,  Buenos Aires, Argentina. mmonteleone@iibintech.com.ar   Introduction: Prenatal stress (PS) exerts strong impact on fetal brain development and on adult offspring brain functions. Previous work demonstrated that chronic stress alters the expression of gm6a, the mRNA for M6a, a glycoprotein involved in neuronal plasticity. Here, we analyzed the effect of PS on gpm6a expression and the epigenetic mechanisms involved. Methods: Pregnant Wistar rats received restraint stress during the last week of pregnancy and male offspring were sacrificed on postnatal days 28 and 60. Hippocampus and prefrontal cortex samples were analyzed for gene expression, methylation status (bisulfite conversion) and protein levels. On the other hand, primary hippocampal neuron cultures were used to analyze microRNA overexpression and histone desacetylase inhibitors (HDACi) effects on M6a levels and neuron morphology. Results: PS induced changes in gpm6a levels in both tissues ages analyzed, indicating a persistent effect. Variations in the methylation pattern at three specific CpGs were found in hippocampus, but not in PFC samples from PS offspring. qPCR measurements showed that PS significantly modified the expression of microRNA-133b in both tissues. Overexpression of this microRNA in neuronal cultures showed a reduction in gmp6a mRNA and protein levels. Moreover filopodium density was also reduced, suggesting that M6a function was affected. Treatment of neurons with a class I HDACi significantly increased M6a levels indicating that HDAC2/3 could be involved in gpm6a regulation. Altogether, these results suggest that PS induce epigenetic changes in brain offspring and that gpm6a may be one of the molecules that translate environmental cues to respond to stress.