{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:46:37Z","timestamp":1790696797488,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,3,19]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      REST (Repressor\u2010Element 1 [RE1]\u2010silencing transcription factor) inhibits Na\n                      <jats:sup>+<\/jats:sup>\n                      \/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      exchanger\u20101 (\n                      <jats:italic>Ncx1<\/jats:italic>\n                      ) transcription in neurons through the binding of RE1 site on brain promoter\n                      <jats:italic>(Br)<\/jats:italic>\n                      after stroke. We identified a new putative RE1 site in\n                      <jats:italic>Ncx1<\/jats:italic>\n                      heart promoter\n                      <jats:italic>(Ht)<\/jats:italic>\n                      sequence (\n                      <jats:italic>Ht<\/jats:italic>\n                      \u2010RE1) that participates in neuronal\n                      <jats:italic>Ncx1<\/jats:italic>\n                      transcription. Because REST recruits DNA\u2010methyltransferase\u20101 (DNMT1) and MeCP2 (methyl\u2010CpG binding protein 2) on different neuronal genes, we investigated the role of this complex in\n                      <jats:italic>Ncx1<\/jats:italic>\n                      transcriptional regulation after stroke.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Luciferase experiments performed in SH\u2010SY5Y cells demonstrated that\n                      <jats:italic>Br<\/jats:italic>\n                      activity was selectively decreased by REST, whereas\n                      <jats:italic>Ht<\/jats:italic>\n                      activity was reduced by DNMT1, MeCP2, and REST. Notably, site\u2010direct mutagenesis of\n                      <jats:italic>Ht\u2010<\/jats:italic>\n                      RE1 prevented REST\u2010dependent downregulation of\n                      <jats:italic>Ncx1<\/jats:italic>\n                      . Furthermore, in temporoparietal cortex of 8\u2010week\u2010old male wild\u2010type mice (C57BL\/6) subjected to transient middle cerebral artery occlusion, DNMT1, MeCP2, and REST binding to\n                      <jats:italic>Ht<\/jats:italic>\n                      promoter was increased, with a consequent DNA promoter hypermethylation. Intracerebroventricular injection of siREST prevented DNMT1\/MeCP2 binding to\n                      <jats:italic>Ht<\/jats:italic>\n                      and\n                      <jats:italic>Ncx1<\/jats:italic>\n                      downregulation, thus causing a reduction in stroke\u2010induced damage. Consistently, in cortical neurons subjected to oxygen and glucose deprivation plus reoxygenation\n                      <jats:italic>Ncx1<\/jats:italic>\n                      knockdown counteracted neuronal protection induced by the demethylating agent 5\u2010azacytidine. For comparisons between 2 experimental groups, Student's\n                      <jats:italic>t<\/jats:italic>\n                      \u00a0test was used, whereas for more than 2 experimental groups, 1\u2010way ANOVA was used, followed by Tukey or Newman Keuls. Statistical significance was set at\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.05.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      If the results of this study are confirmed in humans, it could be asserted that DNMT1\/MeCP2\/REST complex disruption could be a new pharmacological strategy to reduce DNA methylation of\n                      <jats:italic>Ht<\/jats:italic>\n                      in the brain, ameliorating stroke damage.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.123.030460","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T05:54:59Z","timestamp":1709877299000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Stroke Causes DNA Methylation at\n                    <i>Ncx1<\/i>\n                    Heart Promoter in the Brain Via DNMT1\/MeCP2\/REST Epigenetic Complex"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0887-3239","authenticated-orcid":false,"given":"Natascia","family":"Guida","sequence":"first","affiliation":[{"name":"Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine \u201cFederico II\u201d University of Naples Naples 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