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To understand mechanisms that regulate abundant cardiomyocyte (CM)\n                    <jats:italic>TTN<\/jats:italic>\n                    expression, we characterized highly conserved intron 1 sequences that exhibited dynamic changes in chromatin accessibility during differentiation of human CMs from induced pluripotent stem cells (hiPSC-CMs). Homozygous deletion of these sequences in mice caused embryonic lethality, whereas heterozygous mice showed an allele-specific reduction in\n                    <jats:italic>Ttn<\/jats:italic>\n                    expression. A 296 bp fragment of this element, denoted E1, was sufficient to drive expression of a reporter gene in hiPSC-CMs. Deletion of E1 downregulated\n                    <jats:italic>TTN<\/jats:italic>\n                    expression, impaired sarcomerogenesis, and decreased contractility in hiPSC-CMs. Site-directed mutagenesis of predicted binding sites of NK2 homeobox 5 (NKX2-5) and myocyte enhancer factor 2 (MEF2) within E1 abolished its transcriptional activity. In embryonic mice expressing E1 reporter gene constructs, we validated in vivo cardiac-specific activity of E1 and the requirement for NKX2-5\u2013 and MEF2-binding sequences. Moreover, isogenic hiPSC-CMs containing a rare E1 variant in the predicted MEF2-binding motif that was identified in a patient with unexplained dilated cardiomyopathy (DCM) showed reduced TTN expression. Together, these discoveries define an essential, functional enhancer that regulates\n                    <jats:italic>TTN<\/jats:italic>\n                    expression. Manipulation of this element may advance therapeutic strategies to treat DCM caused by\n                    <jats:italic>TTN<\/jats:italic>\n                    haploinsufficiency.\n                  <\/jats:p>","DOI":"10.1172\/jci183353","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T12:00:53Z","timestamp":1734436853000},"source":"Crossref","is-referenced-by-count":10,"title":["Regulation of sarcomere formation and function in the healthy heart requires a titin intronic enhancer"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5978-5779","authenticated-orcid":true,"given":"Yuri","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong 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