biostudies-literatureNassal DMAmerican Heart AssociationNHLBI NIH HHSNational Institutes of Healthe17304https://www.ebi.ac.uk/biostudies/studies/S-EPMC5338919biostudies-literatureUnknown6Arrhythmogenesis from aberrant electrical remodeling is a primary cause of death among patients with heart disease. Amongst a multitude of remodeling events, reduced expression of the ion channel subunit KChIP2 is consistently observed in numerous cardiac pathologies. However, it remains unknown if KChIP2 loss is merely a symptom or involved in disease development. Using rat and human derived cardiomyocytes, we identify a previously unobserved transcriptional capacity for cardiac KChIP2 critical in maintaining electrical stability. Through interaction with genetic elements, KChIP2 transcriptionally repressed the miRNAs miR-34b and miR-34c, which subsequently targeted key depolarizing (<i>I</i>_Na) and repolarizing (<i>I</i>_to) currents altered in cardiac disease. GeneteLifeKChIP2 is a core transcriptional regulator of cardiac excitability.PMC5338919R01 HL096962R01 HL132520HL105338-0113PRE17060106R01HL132520R01HL096962Liu HMaleski DMoravec CSLaurita KRNassal DMRamirez-Navarro AWan XDeschenes IFicker EfalseKChIP2 is a core transcriptional regulator of cardiac excitability.Arrhythmogenesis from aberrant electrical remodeling is a primary cause of death among patients with heart disease. Amongst a multitude of remodeling events, reduced expression of the ion channel subunit KChIP2 is consistently observed in numerous cardiac pathologies. However, it remains unknown if KChIP2 loss is merely a symptom or involved in disease development. Using rat and human derived cardiomyocytes, we identify a previously unobserved transcriptional capacity for cardiac KChIP2 critical in maintaining electrical stability. Through interaction with genetic elements, KChIP2 transcriptionally repressed the miRNAs miR-34b and miR-34c, which subsequently targeted key depolarizing (<i>I</i>_Na) and repolarizing (<i>I</i>_to) currents altered in cardiac disease. Genet2017-01-01T00:00:00Z2017 Mar2026-04-08T17:16:52.62Z2019-03-27T02:37:56ZS-EPMC53389192826370910.7554/eLife.17304