Recent Developments in Cardiovascular Genetics and Genomics
2014; Lippincott Williams & Wilkins; Volume: 115; Issue: 7 Linguagem: Inglês
10.1161/circresaha.114.305054
ISSN1524-4571
Autores Tópico(s)Pluripotent Stem Cells Research
ResumoHomeCirculation ResearchVol. 115, No. 7Recent Developments in Cardiovascular Genetics and Genomics Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRecent Developments in Cardiovascular Genetics and Genomics Ali J. Marian Ali J. MarianAli J. Marian From the Institute of Molecular Medicine, Center for Cardiovascular Genetic Research, University of Texas Health Science Center, Houston. Originally published12 Sep 2014https://doi.org/10.1161/CIRCRESAHA.114.305054Circulation Research. 2014;115:e11–e17IntroductionThe rapid pace of genetic and genomic discoveries in cardiovascular medicine remains unabated. During the past few years, several new causal genes and susceptibility variants for several cardiovascular disease have been identified.1–7 Likewise, genomic and epigenetic discoveries, encompassing noncoding RNAs, DNA methylation, and covalent histone modifications, have shed significant light onto the mechanisms that regulate expression of the cardiovascular phenotypes.5,8–13 Although the main impact of the genetic and genomic discoveries has been in elucidation of the molecular pathogenesis of cardiovascular diseases, recent findings, particularly in single gene discoveries, are also clinically impactful and are becoming increasingly incorporated into the practice of cardiovascular medicine.14–24 In addition, these discoveries have paved the way for genetic-based interventions and gene therapy.25–28 The discoveries have also enabled generation and mechanistic characterization of induced pluripotent stem cell models of genetic cardiovascular diseases.29–35 This progress has been driven in part by the technological advances, most notably the massively parallel nucleic acid sequencing techniques, which have enabled sequencing of the entire human exome, if not the genome, and the whole transcriptome of an individual within a reasonable cost.36,37 The ability to decode an individual exome has also posed a daunting challenge to clinicians and researchers as well as the patients in an accurate identification of the causal or risk variants from the myriad of variants that are present in each exome and in the population.38–40 The plethora of variants in each exome and genome underscores the necessity of incorporating family information in increasing the use of the genetic data and garnering clinically robust and meaningful genetic information.Approaches to the elucidation of genetic causes of cardiovascular diseases have evolved along with the technological advances. Conventional genetic linkage analysis has been all but replaced, complemented, and even supplanted by approaches based on the massively parallel DNA sequencing techniques. Nevertheless, each approach alone or in combinations with others continues to have specific applications and affect our understanding of the genetic basis of cardiovascular disease. Genetic linkage analysis in large families, which led to deciphering the molecular genetic basis of single gene disorders, such as hereditary cardiomyopathies and ion channel disorders,41–44 continues to offer a robust platform for identification of the causal genes for single gene disorders. STAP1, encoding signal transducing adaptor family member 1, was mapped recently through linkage analysis as a novel gene for autosomal dominant familial hypercholesterolemia.45 Further characterization of the locus after exome sequencing and showing evidence of enrichment of the STAP1 variants in an independent cohort with familial hypercholesterolemia supported the causal role of STAP1 in autosomal dominant familial hypercholesterolemia. Therefore, STAP1 joins the previously identified LDLR, APOB, and PCSK9 genes, as the fourth causal gene associated with this rare single gene disorder. Linkage analysis is also frequently applied in a cohort of families and in conjunction with genotyping and sequencing approaches to identify novel loci and genes for cardiovascular disease.46,47 Likewise, Sanger sequencing and massively parallel sequencing techniques, such as whole exome sequencing, are being incorporated in genetic studies including genome-wide association studies (GWAS) to identify the causal genes for cardiovascular phenotypes, such as plasma lipids, lymphedema, and cardiomyopathies.18,46–48 A combined whole exome sequencing and linkage analysis recently led to the identification of RBM20 as a causal gene for autosomal dominant form of dilated cardiomyopathy (DCM) in a large family.49 The findings corroborated the initial reports on RBM20 as a causal gene for DCM.50,51 Given the role of the encoded protein in regulating RNA splicing, the putative mechanism might involve altered splicing of the gene-encoding sarcomere proteins involved in DCM.Genome-Wide Association StudiesGWAS and meta-analysis of GWAS continue to identify genetic variants that predispose to or protect from cardiovascular diseases, influence the response to drug therapy and susceptibility to drug toxicity (http://www.genome.gov/gwastudies/). GWAS by design analyze the known and typically common variants, the latter commonly defined as a variant with a minor allele frequency of ≥0.05.52 The common variants usually exert modest effect sizes and collectively account for a minor fraction of genetic determinants of the complex phenotypes.52,53 Recent GWAS have identified a large number of loci for various cardiovascular phenotypes including plasma cholesterol levels, indices of cardiac structure and function, cardiac conduction and arrhythmias, systemic arterial blood pressure, and pulmonary artery hypertension, among others.54–61 It has also become clearer that variants identified through GWAS are seldom the true causal variants but are either in linkage disequilibrium with another variant in cis or are regulated by distance regulatory elements in trans.62 Recent data have highlighted impact of long-range regulatory interactions of remote DNA sequences in influencing gene expression.63 The long-range interactions result from folding of the genomes into clusters of loops, bringing distant sequences in proximity of each other and hence, trans regulation. These transregulatory effects further complicate identification of the true susceptibility variants for complex phenotypes mapped through the GWAS.Given the relatively modest effects of the common variants and in view of the presence of a large number of rare and private variants in each genome, the current trend is to identify the rare variants with potentially large effect sizes on complex phenotypes using the massively DNA sequencing techniques.64–66 Because of the presence of >13 000 nonsynonymous variants in each exome, massively parallel sequencing-based approaches are more powerful in identification of the risk alleles in the familial settings than in a single individual.67,68 Nevertheless, massively parallel DNA sequencing approaches are also being used in case–control association studies followed by gene-centric analysis of the rare variant to test for enrichment of the variants in the cases. Although a rare variant as opposed to a common variant is expected to have a larger effect size, a few among the several thousand rare variants in each genome would be expected to have clinically discernible effects.52,69 Despite the enthusiasm about the likelihood of a larger effect size of a rare variant, the clinical impact of the rare variants in complex cardiovascular traits has remained largely unknown.MicroRNAsPervasive transcription of the genome into various forms of RNAs, including mRNAs and noncoding RNA, is now well established.70,71 Almost all segments of the mammalian genome is transcribed, albeit in part transiently. Moreover, ≈95% of the multi-exon genes undergoes alternative splicing, resulting in ≈100 000 abundant splice variants in various tissues.72 The most commonly studied and characterized noncoding RNAs are the microRNAs, which tweak and nudge translation of multiple mRNAs. The spectrum of cardiovascular phenotypes that are regulated by the microRNAs continues to expand. Moreover, microRNAs are not only implicated in the pathogenesis but also identified as biomarkers for several cardiovascular diseases.12,73–89 Given that each microRNA targets multiple genes, phenotypic diversity, defined as multiple phenotypes resulting from perturbation of a single microRNA, is not uncommon. Moreover, phenotypic overlap, defined as multiple microRNAs inducing a similar phenotype, is also a common feature. MicroRNA-208 and microRNA-195 were among the first microRNAs that were implicated in regulating cardiac growth and function.90,91 Since then, >2 dozen microRNAs have been implicated in regulating cardiac failure and remodeling, including microRNA-499, microRNA-22, microRNA-133, and microRNA-34a.12,84,92–97 Similarly, a large number of microRNAs are implicated in vascular phenotypes ranging from pulmonary hypertension to aortic aneurysm.77,79,98–107 For example, microRNA-145 was recently shown to be upregulated in the lung tissue of patients with pulmonary hypertension and might be a contributing factor to the pathogenesis of pulmonary hypertension.108 MicroRNA-10, microRNA-15a, microRNA-16, microRNA-26a, microRNA-223, and microRNA-663 are involved in angiogenesis and regulate vascular smooth muscle and endothelial cell phenotypes.76,98,105–107 MicroRNA-29b, microRNA-22, and microRNA-30c are involved in myocardial interstitial fibrosis and heart failure.97,109,110 An intriguing function of microRNAs is in cell-fate determination, differentiation, and cardiac regeneration.73,78,86,89,111,112 Human microRNA-590 and microRNA-199a were found to promote cell cycle re-entry of adult cardiac myocytes in culture and to promote proliferation of cardiac myocytes in neonatal and adult mice, enhancing myocardial recovery post–coronary ligation in mice.89 Similarly, microRNAs are implicated in influencing therapeutic potentials of cardiac progenitor cells.112,113 Moreover, they are also involved in regulating cardiac metabolism and cholesterol biosynthesis.99,103,114,115 In addition, circulating microRNAs have been identified as biomarkers in several cardiovascular conditions, including acute myocardial infarction, coronary artery disease, platelet activation, and heart failure.81,116–120 MicroRNA could also be potential therapeutic targets in several cardiovascular pathological conditions ranging from dyslipidemia to pulmonary hypertension and heart failure.121–124Long Noncoding RNASince the discovery of Braveheart, as a long noncoding RNA (lncRNA) involved in cardiac development,125,126 several lncRNAs have been identified and shown to regulate cardiovascular phenotype.85,127 Braveheart, which does not seem to have an orthologue in the human genome, binds to polycomb repressor complex 2, which is known to regulate normal cardiac development in mice.128 Binding of Braveheart to the polycomb repressor complex 2 complex affects the expression of mesoderm posterior 1, which is an early and transiently expressed transcription factor that regulates the expression of the mesodermal genes, including those involved in cardiovascular development.125,126 Likewise, the lncRNA Fendrr (FOXF1 adjacent noncoding developmental regulatory RNA) targets epigenetic complexes polycomb repressor complex 2 and TRXG/MLL (trithorax group/mixed lineage leukemia) and regulates cardiac gene expression and myocyte differentiation.129 Another lncRNA referred to as cardiac hypertrophy–related factor (CHRF) was recently shown to regulate cardiac hypertrophic response by downregulating microRNA-489, which in turn targets Myd88 transcript.130 A couple of lncRNAs have been shown to regulate smooth muscle cell biology. The lncRNA Cdnkn2b-as, also known as Anril, might be the underpinning molecule responsible for the association of the 9p21 locus with susceptibility to coronary artery disease.131 Similarly, endothelial cell–enriched lncRNA Malat1 has been implicated in angiogenesis.76,132 An intriguing function of a subset of the lncRNAs, in addition to their roles in epigenetic regulation of gene expression and serving as sponges for microRNAs, is coding for small functional peptides.133,134 A notable example is the lncRNA pncr003:2 L, which in Drosophila encodes two 28 and 29 amino acid peptides named sarcolamban A and B.133 Sarcolambans have structural and functional similarities to sarcolipin and phospholamban, which are regulators of Ca+2 uptake by sarcoplasmic reticulum Ca2+ ATPase (SERCA2A) and therefore, regulators of cardiac function.133 The abundance of the lncRNAs in the genome, estimated to be >100 000, has raised considerable interest in functional characterization of the lncRNAs. However, poor evolutionary conservation of the lncRNAs across the species poses considerable challenges in proper identification of their biological functions in relevant animal models. In addition, a careful study design is required to properly recapitulate the temporal and the spatial patterns of expression of the lncRNA of interest to avoid fortuitous effects and delineate actual functions of the lncRNAs.DNA Methylation and Histone Covalent ModificationEpigenetics, beyond the noncoding RNAs, such as DNA methylation and histone covalent modifications, are increasingly recognized as important regulators of gene expression and the resulting cardiovascular phenotypes, ranging from cardiac development to aging. Approximately 70% to 80% of the CpG dinucleotides are methylated in the mammalian genome in most cell types.135 DNA methylation regulates genome stability, transcription, and development.136 The methyl group is deposited by the DNA methyltransferases, which is typically a stable modification. Approximately a quarter of the methylated sites in somatic cells, however, are dynamically regulated during development.135 Differential DNA methylation regions often contain single nucleotide variants (SNVs) and might in part explain association of the SNVs with the specific phenotype found in the GWAS. Recently, the ten-eleven translocation (TET) family enzymes were found to actively demthylate the CpG dinucleotides, a process that might have biological role in embryonic development and stem cell biology.136 DNA methylation is known to regulate the expression of a large number of genes during cardiac development.10 Increased CpG methylation of the genomic DNA isolated from peripheral blood of patients with heart failure and in the DNA isolated from the aortic atherosclerotic plaques has also been reported.137,138 Despite these initial reports, the role of DNA methylation in the pathogenesis of cardiovascular disease remains largely unknown.Post-translational modifications of histone can both activate and silence gene expression through regulating the accessibility of the transcription factors to DNA. Among various post-translational modifications, acetylation and methylation of histones are best studies and established to regulate gene expression. These modifications play essential roles in various biological processes including cardiovascular diseases.139 Acetylation of histones by histone acetyltransferases (HATs) weakens binding of histones to DNA and enhances gene transcription. In contrast, deacetylation by histone deacetylases strengthens the binding of histones to DNA and suppresses gene expression. Histone deacetylases are important regulators of cardiac hypertrophy, interstitial fibrosis, cardiac remodeling, hypertension, and cardiac development among the others.140–146 The current focus is to develop and optimize inhibitors of specific histone deacetylases to achieve specificity to the heart, without encountering considerable untoward systemic effects.Post-translational modifications of histone by methylation afford several functions to chromatins. For example, trimethylation of K4 residue on histone 3 (H3K4me3) identifies promoters and is associated with gene expression. In contrast, H3K27me3 identifies polycomb-repressed regions and H3K9me3 identifies heterochromatin. Poised promoters are identified by a combination of H3K4me3 and H3K27me3, enhancers by H3K4me1 and active enhancers by H3K4me1/H3K27ac.147 Several studies have shown changes in global histone methylation in human heart failure.148,149 Likewise, histone methylation also plays a major role in cardiac myocyte lineage specification.128,150 Deletion of Ezh2 gene, which encodes the EZH2 protein component of the polycomb repressor complex 2, required for trimethylation of H3K27, is associated with developmental cardiac abnormalities and cardiac hypertrophy.128,150 In accordance with the developmental role of histone modifications, de novo mutations in genes encoding histone-modifying proteins have been identified in ≈10% of the cases with congenital heart defects.151 Despite these advances, the full phenotypic spectrum of histone modifications in cardiovascular diseases remains to be elucidated.Repetitive Elements and Heterogeneity of Gene ExpressionSeveral emerging genetic discoveries are also expected to affect cardiovascular medicine in the upcoming years. Notable among them are the increasing recognition of functional role of the repetitive elements, which comprises ≈45% of the human genomes.152,153 These repetitive elements contain 6% to 30% of the transcription initiation sites in the human and mouse genomes and regulate tissue-specific and developmentally regulated gene expression.154 In addition, the repetitive elements could mobilize in the genome and induce insertional mutagenesis through transposition, generate multiple microRNAs, and influence genomic instability.155,156 Retrotransposons are considered major sources of noncoding RNAs.157 The repetitive elements are also implicated in pluripotency maintenance.158 However, their role in cardiovascular diseases is largely unknown.Another noteworthy development is the presence of considerable heterogeneity in gene expression at the cellular level, that is, cell-to-cell variability in gene expression, which is partly recognized because of the capability afforded by the single-cell RNA sequencing techniques.76,159 This heterogeneity is dynamic in nature, as mRNA levels of a given gene of interest could vary within minutes or days, partly based on DNA mechanics.160 The impact of such dynamic variability in cellular mRNA content on phenotypic expression of disease remains unknown.Clustered Regulatory Interspaced Shirt Palindromic RepeatsFinally, clustered regulatory interspaced shirt palindromic repeats (CRISPR) and CRISPR-associated proteins are emerging as powerful tools for genetic engineering.76 Among different CRISPR-Cas systems, the CRISPR-Cas9 technology seems to offer a more suitable profile for genetic manipulations in mammals. Sequence-specific cleavage of nucleic acids is provided by the CRISPR RNAs, which direct a Cas ribonucleoprotein complex to the cognate target on the DNA for cleavage. A recent proof-of-principle study used CRISPR-Cas9 system to knock down expression of PCSK9 in liver and reduce plasma total cholesterol levels in mice.76 Although application of this technology for genetic engineering is in the early stages of development, it has the potential for silencing a mutant allele, introducing a new variant and correcting the underlying genetic mutation. Certainly, there will be more exciting developments in the future.Recent Developments in Cardiovascular Research: The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings. This will enable readers who are not experts in a particular field to grasp the significance and impact of work performed in other fields. It is our hope and expectation that these "Recent Developments" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research. — The EditorsDisclosuresSupported in part by grants from NHLBI (R01-HL088498 and R34HL-105563); Leducq Foundation Trans-Atlantic network of Excellence, TexGen Fund from Greater Houston Community Foundation and George and Mary Josephine Hamman Foundation.FootnotesCorrespondence to Texas Heart Institute, Center for Cardiovascular Genetic Research, University of Texas Health Science Center, 6770 Bertner St, DAC 900A, Houston, TX 77030. E-mail [email protected]References1. 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