Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown(1,2). The Polycomb histone methyltransferase Ezh2 stabilizes transcription by depositing repressive ...marks during development that persist into adulthood(3-9), but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor gene Six1, which functions in cardiac progenitor cells but is stably silenced upon cardiac differentiation. Deletion of Ezh2 in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable gene expression and homeostasis in the postnatal heart. Our results suggest that epigenetic dysregulation in embryonic progenitor cells is a predisposing factor for adult disease and dysregulated stress responses.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This study shows that myocardial fibrosis is an early characteristic of hypertrophic cardiomyopathy caused by sarcomere mutations. The C-terminal propeptide of procollagen type I was shown to be a ...serum biomarker of early myocardial fibrosis.
Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomere proteins.
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With a prevalence of approximately 1 case per 500 persons in the general population, hypertrophic cardiomyopathy is the most common monogenic cardiac disorder.
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The clinical diagnosis depends on the identification of unexplained left ventricular hypertrophy, but this finding is present only in persons with established disease and is typically absent in childhood.
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In contrast, genetic diagnosis identifies pathogenic sarcomere mutations in persons at any age, including mutation carriers with overt hypertrophic cardiomyopathy and mutation carriers without hypertrophy who are at high risk for the development of disease. Studying . . .
This review provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights by physicians who initially detailed ...remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees solved the etiologic riddle of HCM and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis.
Hypertrophic cardiomyopathy is usually caused by mutations in sarcomere proteins, but in some patients such mutations are not found. This study identified mutations in genes encoding enzymes involved ...in glycogen metabolism as causes of hypertrophic cardiomyopathy. Thus, glycogen storage diseases may sometimes present as hypertrophic cardiomyopathy, owing to accumulation of glycogen-filled vacuoles in myocytes.
This study identified mutations in genes encoding enzymes involved in glycogen metabolism as causes of hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy, an autosomal dominant disorder associated with increased morbidity and premature mortality, is traditionally diagnosed on the basis of increased cardiac mass with histopathological findings of myocyte enlargement, myocyte disarray, and cardiac fibrosis.
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However, given the availability of sophisticated noninvasive imaging techniques, an echocardiographic demonstration of unexplained left ventricular hypertrophy constitutes the current basis for a diagnosis of hypertrophic cardiomyopathy.
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Echocardiography has shown that there is considerable diversity in the manifestations of hypertrophic cardiomyopathy, including variable age at onset, from early childhood to late adulthood, and severity of left ventricular hypertrophy. Left ventricular wall thickness in hypertrophic cardiomyopathy . . .
This study shows that mutations in genes previously implicated in adult-onset cardiomyopathy cause 49% of presumed sporadic cases and 64% of familial cases of childhood-onset cardiac hypertrophy. ...These findings indicate that genetic analyses and family evaluations are warranted when childhood-onset hypertrophy is diagnosed.
Mutations in genes previously implicated in adult-onset cardiomyopathy cause 49% of presumed sporadic cases and 64% of familial cases of childhood-onset cardiac hypertrophy.
The diagnosis of childhood cardiomyopathies can be prompted by abnormal physical findings that occur without symptoms or by life-threatening events, including sudden death, which is the presenting manifestation in 3.5% of affected children.
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Despite sophisticated medical management, rates of death and cardiac transplantation among children with symptomatic childhood-onset cardiomyopathy approach 40%.
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The early age at diagnosis and the striking differences in morbidity and mortality that distinguish childhood cardiomyopathies from adult-onset cardiomyopathies have been interpreted to indicate distinct causes of these pathologic conditions.
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Adult-onset hypertrophic cardiomyopathy is a prevalent genetic condition caused by inherited or new mutations in . . .
Somatic mtDNA mutations have been reported in some human tumors, but their spectrum in different malignancies and their role in cancer development remain incompletely understood. Here, we describe ...the breadth of somatic and inherited mutations across the mitochondrial genome by sequence analyses of paired tumor and normal tissue samples from 226 individuals with five types of cancer using whole-genome data generated by The Cancer Genome Atlas Research Network. The frequencies of deleterious tumor-specific somatic mutations found in mtDNA varied across tumor types, ranging from 13% of glioblastomas to 63% of rectal adenocarcinomas. Compared with inherited mtDNA variants, somatic mtDNA mutations were enriched for nonsynonymous vs. synonymous changes (93 vs. 15; P < 2.2E−16) and were predicted to functionally impact the encoded protein. Somatic missense mutations in tumors were distributed uniformly among the mitochondrial protein genes, but 65% of somatic truncating mutations occurred in NADH dehydrogenase 5. Analysis of staging data in colon and rectal cancers revealed that the frequency of damaging mitochondrial mutations is the same in stages I and IV tumors. In summary, these data suggest that damaging somatic mtDNA mutations occur frequently (13–63%) in these five tumor types and likely confer a selective advantage in oncogenesis.
Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but ...the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
Human mutations that truncate the massive sarcomere protein titin TTN-truncating variants (TTNtvs) are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure ...and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell–derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
Activation of complex molecular programs in specific cell lineages governs mammalian heart development, from a primordial linear tube to a four-chamber organ. To characterize lineage-specific, ...spatiotemporal developmental programs, we performed single-cell RNA sequencing of >1,200 murine cells isolated at seven time points spanning embryonic day 9.5 (primordial heart tube) to postnatal day 21 (mature heart). Using unbiased transcriptional data, we classified cardiomyocytes, endothelial cells, and fibroblast-enriched cells, thus identifying markers for temporal and chamber-specific developmental programs. By harnessing these datasets, we defined developmental ages of human and mouse pluripotent stem-cell-derived cardiomyocytes and characterized lineage-specific maturation defects in hearts of mice with heterozygous mutations in Nkx2.5 that cause human heart malformations. This spatiotemporal transcriptome analysis of heart development reveals lineage-specific gene programs underlying normal cardiac development and congenital heart disease.
•Single-cell RNA-seq data characterizing >1,200 murine cells from E9.5–P21 hearts•Dynamic spatiotemporal gene expression defines distinct cardiomyocyte populations•Human/mouse stem-cell-derived cardiomyocytes are developmentally immature•Nkx2.5+/− mice have lineage-specific maturation defects in cardiac cells
Using spatiotemporal RNA-seq analyses of single cells isolated from E9.5–P21 mouse hearts, DeLaughter, Bick et al. reveal the dynamic transcriptional programs directing cardiomyocyte maturation during heart development. These data provide benchmarks for assessing lineage-specific maturation of differentiated stem cells and a basis for interrogating how human mutations cause congenital heart malformations.
Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we ...report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant$Arg \rightarrow Cys$missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular$Ca^2+-adenosine$triphosphatase (SERCA2a) pump. Transgenic$PLN^{R9C}$mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN,$PLN^{R9C}$did not directly inhibit SERCA2a. Rather,$PLN^{R9C}$trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.
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