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Cardiac epigenomics

Bernard Thienpont, Jan Magnus Aronsen, Emma Louise Robinson, Hanneke Okkenhaug, Elena Loche, Arianna Ferrini, Patrick Brien, Kanar Alkass, Antonio Tomasso, Asmita Agrawal, Olaf Bergmann, Ivar Sjaastad, Wolf Reik, Hywel Llewelyn Roderick
Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes...
November 28, 2016: Journal of Clinical Investigation
Peter F Davies, Elisabetta Manduchi, Christian J Stoeckert, Yi-Zhou Jiang
Hemodynamics creates a constantly changing physical and chemical environment to which the arterial endothelium is exquisitely sensitive. Biomechanical stresses are intrinsic to blood flow characteristics and blood pressure and therefore are important considerations in hypertension. Near branching anatomical sites in arteries, blood flow separates from the main flow to undergo complex multi-directional characteristics for a part of each cardiac cycle (collectively referred to as disturbed flow). Atherosclerosis and aneurysmal pathology develop preferentially at disturbed flow locations, particularly when an additional cardiovascular risk factor such as hypercholesterolemia or high blood pressure are present...
September 2016: Journal of Hypertension
Diane E Dickel, Iros Barozzi, Yiwen Zhu, Yoko Fukuda-Yuzawa, Marco Osterwalder, Brandon J Mannion, Dalit May, Cailyn H Spurrell, Ingrid Plajzer-Frick, Catherine S Pickle, Elizabeth Lee, Tyler H Garvin, Momoe Kato, Jennifer A Akiyama, Veena Afzal, Ah Young Lee, David U Gorkin, Bing Ren, Edward M Rubin, Axel Visel, Len A Pennacchio
Whole-genome sequencing is identifying growing numbers of non-coding variants in human disease studies, but the lack of accurate functional annotations prevents their interpretation. We describe the genome-wide landscape of distant-acting enhancers active in the developing and adult human heart, an organ whose impairment is a predominant cause of mortality and morbidity. Using integrative analysis of >35 epigenomic data sets from mouse and human pre- and postnatal hearts we created a comprehensive reference of >80,000 putative human heart enhancers...
October 5, 2016: Nature Communications
Florence Pagé-Larivière, Amélie Tremblay, Céline Campagna, Manuel J Rodriguez, Marc-André Sirard
Bromodichloromethane (BDCM) is one of the trihalomethanes present in chlorinated water. Humans are thus daily exposed. Previous contradictory results failed to clearly establish the adverse effects of low concentrations of BDCM. By using the porcine preimplantation embryo as a sensitive model, we showed that exposure to low concentrations of BDCM (10 and 100ppb) during the first week of embryo development induced adverse effect on the blastocyst rate and alteration of the estradiol pathway. Our results also suggest that blastocysts exposed to BDCM present transcriptomic and epigenomic adaptive modifications compatible with the cardiac anomalies observed by previous studies of newborns exposed to BDCM during gestation...
September 23, 2016: Reproductive Toxicology
Mathias Rask-Andersen, David Martinsson, Muhammad Ahsan, Stefan Enroth, Weronica E Ek, Ulf Gyllensten, Åsa Johansson
Cardiovascular diseases (CVDs) are the leading causes of death worldwide and represent a substantial economic burden on public health care systems. Epigenetic markers have potential as diagnostic markers before clinical symptoms have emerged, and as prognostic markers to inform the choice of clinical intervention. In this study, we performed an epigenome-wide association study (EWAS) for CVDs, to identify disease-specific alterations in DNA methylation. CpG methylation in blood samples from the northern Sweden population health study (NSPHS) (n = 729) was assayed on the Illumina Infinium HumanMethylation450 BeadChip...
September 15, 2016: Human Molecular Genetics
Xin Chen, Tushar Chakravarty, Yiqiang Zhang, Xiaojin Li, Jiang F Zhong, Charles Wang
The molecular basis underlying the dedifferentiation of mammalian adult cardiomyocytes (ACMs) into myocyte-derived cardiac progenitor cells (mCPCs) during cardiac tissue regeneration is poorly understood. We present data integrating single-cell transcriptome and whole-genome DNA methylome analyses of mouse mCPCs to understand the epigenomic reprogramming governing their intrinsic cellular plasticity. Compared to parental cardiomyocytes, mCPCs display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome...
September 13, 2016: Scientific Data
Matthew Ackers-Johnson, Peter Yiqing Li, Andrew P Holmes, Sian-Marie O'Brien, Davor Pavlovic, Roger S Foo
RATIONALE: Cardiovascular disease represents a global pandemic. The advent of and recent advances in mouse genomics, epigenomics, and transgenics offer ever-greater potential for powerful avenues of research. However, progress is often constrained by unique complexities associated with the isolation of viable myocytes from the adult mouse heart. Current protocols rely on retrograde aortic perfusion using specialized Langendorff apparatus, which poses considerable logistical and technical barriers to researchers and demands extensive training investment...
September 30, 2016: Circulation Research
Marcel Grunert, Cornelia Dorn, Huanhuan Cui, Ilona Dunkel, Kerstin Schulz, Sophia Schoenhals, Wei Sun, Felix Berger, Wei Chen, Silke R Sperling
AIMS: For the majority of congenital heart diseases (CHDs), the full complexity of the causative molecular network, which is driven by genetic, epigenetic, and environmental factors, is yet to be elucidated. Epigenetic alterations are suggested to play a pivotal role in modulating the phenotypic expression of CHDs and their clinical course during life. Candidate approaches implied that DNA methylation might have a developmental role in CHD and contributes to the long-term progress of non-structural cardiac diseases...
October 2016: Cardiovascular Research
Emma Monte, Manuel Rosa-Garrido, Elaheh Karbassi, Haodong Chen, Rachel Lopez, Christoph D Rau, Jessica Wang, Stanley F Nelson, Yong Wu, Enrico Stefani, Aldons J Lusis, Yibin Wang, Siavash K Kurdistani, Sarah Franklin, Thomas M Vondriska
Transcriptome remodeling in heart disease occurs through the coordinated actions of transcription factors, histone modifications, and other chromatin features at pathology-associated genes. The extent to which genome-wide chromatin reorganization also contributes to the resultant changes in gene expression remains unknown. We examined the roles of two chromatin structural proteins, Ctcf (CCCTC-binding factor) and Hmgb2 (high mobility group protein B2), in regulating pathologic transcription and chromatin remodeling...
July 22, 2016: Journal of Biological Chemistry
Xinchen Wang, Nathan R Tucker, Gizem Rizki, Robert Mills, Peter Hl Krijger, Elzo de Wit, Vidya Subramanian, Eric Bartell, Xinh-Xinh Nguyen, Jiangchuan Ye, Jordan Leyton-Mange, Elena V Dolmatova, Pim van der Harst, Wouter de Laat, Patrick T Ellinor, Christopher Newton-Cheh, David J Milan, Manolis Kellis, Laurie A Boyer
Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies...
2016: ELife
Yang Wang, Yuejiao Li, Chen Guo, Qin Lu, Weiping Wang, Zhuqing Jia, Ping Chen, Kangtao Ma, Danny Reinberg, Chunyan Zhou
ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However, the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream target genes that are implicated in cardiac differentiation, through an epigenetic mechanism...
August 19, 2016: Nucleic Acids Research
Scot J Matkovich
PURPOSE OF REVIEW: Genome-wide analysis of RNA abundances (transcriptome analysis) offers great potential to identify biomarkers of disease and to gain insight into mechanisms underlying the development of heart failure. I will discuss key factors in generating and evaluating transcriptome data, and recent studies that have contributed to the understanding of cardiac disease in humans and animal models. RECENT FINDINGS: Thorough assessments of RNA-sequencing performance performed across multiple laboratories have demonstrated its primacy in measuring differential RNA abundances, due in part to its wide dynamic range and accuracy...
May 2016: Current Opinion in Cardiology
Yingmei Zhang, Jun Ren
Uncorrected obesity has been associated with cardiac hypertrophy and contractile dysfunction. Several mechanisms for this cardiomyopathy have been identified, including oxidative stress, autophagy, adrenergic and renin-angiotensin aldosterone overflow. Another process that may regulate effects of obesity is epigenetics, which refers to the heritable alterations in gene expression or cellular phenotype that are not encoded on the DNA sequence. Advances in epigenome profiling have greatly improved the understanding of the epigenome in obesity, where environmental exposures during early life result in an increased health risk later on in life...
May 2016: Pharmacology & Therapeutics
Chunjiang He, Hanyang Hu, Kitchener D Wilson, Haodi Wu, Jing Feng, Siyu Xia, Jared Churko, Kun Qu, Howard Y Chang, Joseph C Wu
BACKGROUND: The molecular regulation of heart development is regulated by cis- and trans-factors acting on the genome and epigenome. As a class of important regulatory RNAs, the role of long noncoding RNAs (lncRNAs) in human heart development is still poorly understood. Furthermore, factors that interact with lncRNAs in this process are not well characterized. METHODS AND RESULTS: Using RNA sequencing, we systematically define the contrasting lncRNA expression patterns between fetal and adult hearts...
April 2016: Circulation. Cardiovascular Genetics
Gregory A Quaife-Ryan, Choon Boon Sim, Enzo R Porrello, James E Hudson
In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyocytes following modulation of these factors rarely reaches neonatal levels...
October 2016: Seminars in Cell & Developmental Biology
Yiqiang Zhang, Jiang F Zhong, Hongyu Qiu, W Robb MacLellan, Eduardo Marbán, Charles Wang
It has been believed that mammalian adult cardiomyocytes (ACMs) are terminally-differentiated and are unable to proliferate. Recently, using a bi-transgenic ACM fate mapping mouse model and an in vitro culture system, we demonstrated that adult mouse cardiomyocytes were able to dedifferentiate into cardiac progenitor-like cells (CPCs). However, little is known about the molecular basis of their intrinsic cellular plasticity. Here we integrate single-cell transcriptome and whole-genome DNA methylation analyses to unravel the molecular mechanisms underlying the dedifferentiation and cell cycle reentry of mouse ACMs...
December 14, 2015: Scientific Reports
Avinash Das, Michael Morley, Christine S Moravec, W H W Tang, Hakon Hakonarson, Kenneth B Margulies, Thomas P Cappola, Shane Jensen, Sridhar Hannenhalli
The standard expression quantitative trait loci (eQTL) detects polymorphisms associated with gene expression without revealing causality. We introduce a coupled Bayesian regression approach--eQTeL, which leverages epigenetic data to estimate regulatory and gene interaction potential, and identifies combination of regulatory single-nucleotide polymorphisms (SNPs) that explain the gene expression variance. On human heart data, eQTeL not only explains a significantly greater proportion of expression variance but also predicts gene expression more accurately than other methods...
October 12, 2015: Nature Communications
Marta Lombó, Cristina Fernández-Díez, Silvia González-Rojo, Claudia Navarro, Vanesa Robles, María Paz Herráez
Bisphenol A (BPA) is an endocrine disruptor used in manufacturing of plastic devices, resulting in an ubiquitous presence in the environment linked to human infertility, obesity or cardiovascular diseases. Both transcriptome and epigenome modifications lie behind these disorders that might be inherited transgenerationally when affecting germline. To assess potential effects of paternal exposure on offspring development, adult zebrafish males were exposed to BPA during spermatogenesis and mated with non-treated females...
November 2015: Environmental Pollution
Thomas G Di Salvo
INTRODUCTION: Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial. AREAS COVERED: This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering...
2015: Expert Opinion on Biological Therapy
Adam B Stein, Sascha N Goonewardena, Thomas A Jones, Parker J Prusick, Ahmad A Bazzi, Jane M Belyavskaya, Makayla M McCoskey, Rachel A Dandar
Pressure overload induces stress-induced signaling pathways and a coordinated transcriptional response that begets concentric cardiac hypertrophy. Although concentric hypertrophy initially attenuates wall stress and maintains cardiac function, continued stress can result in maladaptive cardiac remodeling. Cardiac remodeling is orchestrated by transcription factors that act within the context of an epigenetic landscape. Since the epigenetic landscape serves as a molecular link between environmental factors (stress) and cellular phenotype (disease), defining the role of the epigenome in the development and progression of cardiac remodeling could lead to new therapeutic approaches...
2015: PloS One
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