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Retrospective studies in temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood, followed by a silent period where epileptogenesis occurs to end up in chronic epilepsy. Epileptogenesis, the process through which a normal brain undergoes structural and functional changes leading to epilepsy, is not completely understood. We hypothesized that epigenetics may be involved in epileptogenesis, specifically affecting astrocytes through pathological remodeling. To study this process, we used three approaches: the lithium\u2013pilocarpine model of TLE in rats, primary astroglial cultures exposed to epileptogenic DAMP named HMGB1, and brain tissue samples resected from TLE patients with drug-resistant epilepsy. We found that the IPE achieved by lithium\u2013pilocarpine treatment (127\/30\u00a0mg\/kg IP) induced the DNA methylation of astrocytes at 7-, 21-, and 35-days post-IPE, indicating persistent epigenetic alterations in astrocytes during the epileptogenic period. In addition, we observed the down-regulation of homeostatic astroglial genes, including AQP4, glutamine synthase (GS), and Kir4.1, along with increased expression of proinflammatory genes (C3, MAFG) and DNA methyltransferases (DNMT). These alterations were mimicked in primary astrocyte cultures exposed to the epileptogenic HMGB1 (500\u00a0ng\/ml; 18\u00a0h), which resulted in the hypermethylation of homeostatic astroglial genes and repression of homeostatic genes. HMGB1-induced repression of astroglial homeostatic genes was prevented by the treatment with DNMT inhibitor decitabine. Interestingly, astrocytes from TLE patients brains showed reactive astrogliosis, increased DNA methylation, and down-regulation of homeostatic genes Kir4.1 and GS. Taken together, these findings show that astrocytes are pathologically altered during the epileptogenic period by epigenetic modifications, combining the proinflammatory gain of function with the loss of homeostatic profile. This may contribute to the long-term alterations underlying epileptogenesis.<\/jats:p>","DOI":"10.1042\/cs20256367","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T07:44:16Z","timestamp":1768808656000},"page":"221-237","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis"],"prefix":"10.1042","volume":"140","author":[{"given":"Dante","family":"G\u00f3mez Cuautle","sequence":"first","affiliation":[{"name":"1Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, Facultad de Medicina, Universidad de Buenos Aires-CONICET, (1121) Ciudad de Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Rossi","sequence":"additional","affiliation":[{"name":"1Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, Facultad de Medicina, Universidad de Buenos Aires-CONICET, (1121) Ciudad de Buenos Aires, Argentina"},{"name":"2Departamento de Histolog\u00eda, Embriolog\u00eda, Biolog\u00eda Celular y Gen\u00e9tica, Facultad de Medicina, Universidad de Buenos Aires (UBA), (1121) Ciudad de Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton\u00a0Paul","family":"M\u00e1rquez Cadena","sequence":"additional","affiliation":[{"name":"1Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, Facultad de Medicina, Universidad de Buenos Aires-CONICET, (1121) Ciudad de Buenos Aires, Argentina"},{"name":"2Departamento de Histolog\u00eda, Embriolog\u00eda, Biolog\u00eda Celular y Gen\u00e9tica, Facultad de Medicina, Universidad de Buenos Aires (UBA), (1121) Ciudad de Buenos Aires, Argentina"},{"name":"3Instituto Tecnol\u00f3gico de Buenos Aires (ITBA), Ciudad de Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Villarreal","sequence":"additional","affiliation":[{"name":"1Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, Facultad de Medicina, Universidad de Buenos Aires-CONICET, (1121) Ciudad de Buenos Aires, Argentina"},{"name":"3Instituto Tecnol\u00f3gico de Buenos Aires (ITBA), Ciudad de Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"D'Alessio","sequence":"additional","affiliation":[{"name":"1Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, Facultad de Medicina, Universidad de Buenos Aires-CONICET, (1121) Ciudad de Buenos Aires, Argentina"},{"name":"4Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad de Buenos Aires (UBA), Centro de Epilepsia, Hospital de Agudos \u201cJ. M. Ramos Mej\u00eda\u201d, (1221) Ciudad de Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4009-6337","authenticated-orcid":false,"given":"Alberto\u00a0Javier","family":"Ramos","sequence":"additional","affiliation":[{"name":"1Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, Facultad de Medicina, Universidad de Buenos Aires-CONICET, (1121) Ciudad de Buenos Aires, Argentina"},{"name":"3Instituto Tecnol\u00f3gico de Buenos Aires (ITBA), Ciudad de Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"2026021107473151400_B1","doi-asserted-by":"publisher","first-page":"re12","DOI":"10.1126\/stke.3562006re12","article-title":"Molecular signaling mechanisms underlying epileptogenesis","volume":"2006","author":"McNamara","year":"2006","journal-title":"Sci. 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