This book describes important advances in our understanding of how environmental conditions affect cardiac gene expression through epigenetic mechanisms. Further, it discusses the roles of chromatin modifications (in particular DNA methylation and histone modifications) and of chromatin regulators in the context of cardiac diseases. The book provides readers with an overview of our current understanding of epigenetic regulation in the heart, and will stimulate further research in this exciting field. Edited and written by internationally respected experts, it addresses the needs of professors, students and researchers working in the fields of cardiac biology and epigenetics.

Epigenetics in Cardiovascular Disease, a new volume in the Translational Epigenetics series, offers a comprehensive overview of the epigenetics mechanisms governing cardiovascular disease development, as well as instructions in research methods and guidance in pursing new studies. More than thirty international experts provide an (i) overview of the epigenetics mechanisms and their contribution to cardiovascular disease development, (i) high-throughput methods for RNA profiling including single-cell RNA-seq, (iii) the role of nucleic acid methylation in cardiovascular disease development, (iv) epigenetic actors as biomarkers and drug targets, (v) and the potential of epigenetics to advance personalized medicine. Here, readers will discover strategies to combat research challenges, improve quality of their epigenetic research and reproducibility of their findings. Additionally, discussion of assay and drug development for personalized healthcare pave the way for a new era of understanding in cardiovascular disease. Offers a thorough overview of role of epigenetics mechanisms in cardiovascular disease Includes guidance to improve research plans, experimental protocols design, quality and reproducibility of results in new epigenetics research Explores biomarkers and drug targets of therapeutic potential to advance personalized healthcare Features chapter contributions from a wide range of international researchers in the field

What lies at the heart of neuronal plasticity? Accumulating evidence points to epigenetics. This word originally indicated potentially heritable modifications in gene expression that do not involve changes in DNA sequence. Today this definition is much less strict, and epigenetic control is thought to include DNA methylation, histone modifications, histone variants, microRNA metabolic pathways and non-histone proteins modifications. Thus, while neuronal plasticity is rightly thought to be intimately associated to genomic control, it is critical to appreciate that there is much more to the genome than DNA sequence. Recent years have seen spectacular advances in the field of epigenetics. These have attracted the interest of researchers in many fields and evidence connecting epigenetic regulation to brain functions has been accumulating. Neurons daily convert a variety of external stimuli into rapid or long-lasting changes in gene expression. A variety of studies have centered on the molecular mechanisms implicated in epigenetic control and how these may operate in concert. It will be critical to unravel how specificity is achieved. Importantly, specific modifications seem to mediate both developmental processes and adult brain functions, such as synaptic plasticity and memory. Many aspects of the research in neurosciences and endocrinology during the upcoming decade will be dominated by the deciphering of epigenetic control. This book constitutes a compendium of the most updated views in the field.

Under pathological stress, an otherwise healthy heart may enter hypertrophy, a partially-reversible, compromised state wherein heart function is relatively normal although the muscle cells increase in size. Should the stress continue, however, the heart will succumb to the irreversible condition of heart failure, resulting in an inability to efficaciously pump enough blood to support bodily demands. When the heart enters states of either hypertrophy or failure, noticeable changes in chromatin accessibility and gene expression arise. Chromatin accessibility can be defined by a binary chromatin state model: heterochromatin is tightly packed and contains silenced genes, while the relatively loose conformation of euchromatin is more conductive to active gene transcription. Alternations in gene expression or epigenetic regulation are revealed using high-throughput sequencing techniques, which have been developed and rigorously applied over the last two decades. How the principles revealed from studies of chromatin impact gene expression levels in the diseased heart is unknown. My dissertation studied the role of multiple chromatin regulator factors, as studied by high-throughput sequencing techniques, contribute to function of the normal and diseased heart. Those factors include a histone modifying enzyme, a nucleosome remodeling protein, circular RNAs and DNA methylation. The first two chapters of my dissertation detail the functions of two chromatin remodelers identified by quantitative proteomics using mouse hypertrophy and heart failure models: Smyd1, a histone methyltransferase coding gene containing the SET and MYND domains, and Napl14, nucleosome assembly protein 1-like 4. Chapter 1 reports that the chromatin-binding protein Smyd1 restricts adult mammalian heart growth. Mice with induced knockdown of cardiac-specific Smyd1 displayed cardiomyocyte growth, organ remodeling, and declined heart function. Chapter 2 describes a possible mechanism by which histone chaperone Nap1l4 may regulate cardiac transcription in hypertrophy. As revealed by siRNA knock down, the lack of Nap1l4-mediated transcription reduces the size of neonatal rat ventricular myocytes (NRVMs) and inhibits fetal gene reprogramming induced by phenylephrine (PHE). However, when Nap1l4 is overexpressed, there is an increase in the size of NRVMs. The latter two chapters of the dissertation describe the epigenomic changes revealed by high-throughput sequencing that could potentially affect gene expression during cardiovascular diseases. Chapter 3 explores our utilization of Ribo-Zero RNA sequencing to discover circular RNAs (circRNAs) in the heart using mouse models. We confirmed the existence of cardiac-related circRNAs including circMyocd, circRyr2, and circTtn. With the successful knockdown of circMyocd in NRVMs, we observed increased expression of linear Myocd, indicating the circRNAs may regulate transcription of its linear counterparts. Chapter 4 characterizes DNA methylation alterations in patients undergoing coronary artery bypass grafting (CABG) using reduced representation bisulfite sequencing (RRBS) with respect to post-operative atrial fibrillation (POAF). When comparing pre-operative and post-operative epigenomic states, we found that the hypervariable CpG sites are mostly enriched in or around genes pertaining to the immune system, cellular adhesion and the cardiovascular system. Specifically, altered CpG methylation in genes coding for transforming growth factor-beta 1 (TGF- 1) may be a marker for POAF as well as pre-operative and post-operative epigenomic states. My dissertation revealed that epigenetic changes including chromatin remodelers, DNA methylation and circRNAs could affect the gene expression during heart diseases. The work will undoubtedly benefit the whole community and shed light on the translational medicine for heart failure patients.

Circadian rhythm influences the regulation of homeostasis and physiological processes, and its disruption could lead to metabolic disorders and cardiovascular diseases (CVD). CVDs are still the dominant cause of death worldwide, which are related to numerous environmental and hereditary risk factors. Environmental and hereditary factors can clarify a small fraction of the CVD risk discrepancy. Epigenomics is a very bright strategy that will complement the knowledge of the genetic basis of CVDs. Epigenetic mechanisms allow cells to reply promptly to environmental changes and include DNA methylation, histone modification, and noncoding RNA alterations. According to research data, the circadian rhythm regulates many epigenetic regulators. The challenge is to understand how epigenetic events happen rhythmically in tissues that are involved in the development of CVDs. Epigenetic events are possibly reversible through their interface with environmental and nutritional factors, allowing innovative preventive and therapeutic strategies in cardiovascular diseases.