title: DOT1L regulates dystrophin expression and is critical for cardiac function.
abstract: Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin-glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease.
authors.affiliation: Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Anh T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Bin
authors.initials: B
authors.lastname: Xiao
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Neppl
authors.forename: Eric M
authors.initials: EM
authors.lastname: Kallin
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002460:Cell Line; D015536:Down-Regulation; D016189:Dystrophin / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism
chemical_list: D016189:Dystrophin; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase