Pilocarpine-induced seizures associate with modifications of LSD1/CoREST/HDAC1/2 epigenetic complex and repressive chromatin in mice hippocampus

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dc.contributor.authorNoches, Veronica
dc.contributor.authorRivera, Carlos
dc.contributor.authorGonzalez, Marcela P.
dc.contributor.authorMerello, Gianluca
dc.contributor.authorOlivares-Costa, Montserrat
dc.contributor.authorEstela Andres, Maria
dc.date.accessioned2025-01-20T23:53:50Z
dc.date.available2025-01-20T23:53:50Z
dc.date.issued2021
dc.description.abstractEpilepsy is a neurological disorder of genetic or environmental origin characterized by recurrent spontaneous seizures. A rodent model of temporal lobe epilepsy is induced by a single administration of pilocarpine, a nonselective cholinergic muscarinic receptor agonist. The molecular changes associated with pilocarpine-induced seizures are still poorly described. Epigenetic multiprotein complexes that regulate gene expression by changing the structure of chromatin impose transcriptional memories. Among the epigenetic enzymes relevant to the epileptogenic process is lysine-specific demethylase 1 (LSD1, KDM1A), which regulates the expression of genes that control neuronal excitability. LSD1 forms complexes with the CoREST family of transcriptional corepressors, which are molecular bridges that bring HDAC1/2 and LSD1 enzymes to deacetylate and demethylate the tail of nucleosomal histone H3. To test the hypothesis that LSD1-complexes are involved in initial modifications associated with pilocarpine-induced epilepsy, we studied the expression of main components of LSD1-complexes and the associated epigenetic marks on isolated neurons and the hippocampus of pilocarpine-treated mice. Using a single injection of 300 mg/kg of pilocarpine and after 24 h, we found that protein levels of LSD1, CoREST2, and HDAC1/2 increased, while CoREST1 decreased in the hippocampus. In addition, we observed increased histone H3 lysine 9 di- and trimethylation (H3K9me2/3) and decreased histone H3 lysine 4 di and trimethylation (H3K4me2/3). Similar findings were observed in cultured hippocampal neurons and HT-22 hippocampal cell line treated with pilocarpine. In conclusion, our data show that muscarinic receptor activation by pilocarpine induces a global repressive state of chromatin and prevalence of LSD1-CoREST2 epigenetic complexes, modifications that could underlie the pathophysiological processes leading to epilepsy.
dc.description.funderNational Agency for Research and Development (ANID), Chile (FONDECYT)
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.bbrep.2020.100889
dc.identifier.issn2405-5808
dc.identifier.urihttps://doi.org/10.1016/j.bbrep.2020.100889
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94999
dc.identifier.wosidWOS:000646693800018
dc.language.isoen
dc.revistaBiochemistry and biophysics reports
dc.rightsacceso restringido
dc.subjectPilocarpine
dc.subjectStatus epilepticus
dc.subjectLCH complex
dc.subjectH3K4me2
dc.subjectH3K9me2
dc.subjectMuscarinic receptors
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePilocarpine-induced seizures associate with modifications of LSD1/CoREST/HDAC1/2 epigenetic complex and repressive chromatin in mice hippocampus
dc.typeartículo
dc.volumen25
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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