{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:52:53Z","timestamp":1788972773262,"version":"build-2803163510"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Sustained pathological cardiac hypertrophy eventually leads to heart failure; however, there is currently no effective therapeutic approach. Epigenetic dysregulation, including histone modification alterations, is implicated in cardiac hypertrophy development. Yet, the detailed mechanisms are not completely elucidated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Nano-HPLC-MS\/MS (nano-scale high-performance liquid chromatography-tandem mass spectrometry) was conducted to analyze histone modifications. Cardiomyocyte-specific Dot1L (disruptor of telomeric silencing 1-like) knockout and transgenic mice were generated to evaluate the function of Dot1L in cardiac hypertrophy. Stress was induced in mice by transverse aortic constriction or continuous isoproterenol infusion. RNA-sequencing and chromatin immunoprecipitation sequencing were combined and analyzed to identify the direct transcriptional target of Dot1L, which was verified by multiple molecular biological methodologies. Primary neonatal rat ventricle myocytes were used to identify potential targets and study the molecular mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>Histone H3K79 dimethylation and its specific methyltransferase Dot1L were upregulated in hypertrophic stimuli-treated cardiomyocytes, cardiac tissues from pressure overload\u2013stressed mice, and patients with hypertrophic cardiomyopathy. The ablation of Dot1L in cardiomyocytes of adult mice protected against pressure overload\u2013induced hypertrophy. Chromatin immunoprecipitation sequencing assay and genome-wide transcriptional analysis showed that Dot1L-catalyzed H3K79 dimethylation promoted the expression of transcription factor Tbx6 in stressed neonatal rat ventricle myocytes. Knockdown of Tbx6 (T-box transcription factor 6) abolished Dot1L overexpression-exaggerated cardiac hypertrophy in mice in response to pressure overload. The Dot1L inhibitor SGC0946 treatment markedly improved isoproterenol-induced cardiac hypertrophy in mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Dot1L\u2013H3K79 dimethylation\u2013Tbx6 axis facilitates pressure overload\u2013induced cardiac hypertrophy. Targeting Dot1L may be a promising therapeutic strategy for heart failure.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.324940","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T05:00:16Z","timestamp":1751259616000},"page":"496-512","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Dot1L Promotes Stress-Induced Cardiac Hypertrophy in Mice via Tbx6"],"prefix":"10.1161","volume":"137","author":[{"given":"Jiao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences (J.L., S.Z., C.M., B.W., D.H., Q.L., Y.Y.), Tianjin Medical University, China."},{"name":"Department of Cardiology, First Affiliated Hospital of Zhengzhou University, China (J.L., Y.J., J.Z., 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