Epigenetics

In this issue we focus on the topic of Epigenetics, the study of heritable phenotypic traits not encoded by the genetic sequence. While every cell in your body has a copy of your genetic code in the form of DNA, many of the unique features between different cell types and between different individuals arise from unique patterns of gene expression. In recent decades, it has become increasingly clear that these traits are dictated by an extra layer of information which is inheritable but not directly encoded in the genetic sequence: hence the prefix, “epi-” from the Greek “on top of” or “outside of.” Epigenetic information can be encoded in a variety of ways, altering chromosomes in order to favor expression or silencing of certain genes in response to cellular signals, environmental factors, or developmental cues. Importantly, cells have a variety of enzymes and mechanisms responsible for maintaining the epigenetic state throughout the cell’s life cycle and reproduction, allowing these patterns of expression to be inherited. The molecular mechanisms of epigenetics typically involve physical or chemical modifications of the chromosomes. In the nucleus, the DNA is wrapped around histone proteins, providing a structural scaffold to tightly condense the genome for storage and requiring biochemical regulation to provide access for transcribing genes. Chemical modifications to the histone proteins or the DNA molecules can recruit specific binding proteins or alter the physical arrangement of the chromosome. On top of that, regulatory interactions of non-coding RNAs, which are transcribed but function without coding for proteins, can provide an additional layer of control on transcription and translation across the genome. The field of epigenetics has seen a rapid expansion in recent years, as new techniques have allowed researchers to precisely measure broad patterns of gene expression and to probe the locations of specific epigenetic marks and DNAbinding proteins. By addressing how these marks are initiated and maintained and how they result in observable phenotypic traits, researchers can uncover new modes of regulation and complex interactions. Studies of epigenetic mechanisms have enabled insights into human development (such as stem cell maintenance and tissue differentiation) and diseases (especially cancers) and provide promising targets for therapeutic approaches. In this issue of the Yale Journal of Biology and Medicine, we present articles spanning the breadth and depth of epigenetics research, either focusing on the wide variety of roles of a particular mechanism (such as a type of non-coding RNA) or investigating the assortment of mechanisms at play in a particular case (such as a certain cancer or cell type). First in this issue, Connelly et al. present an original research article investigating the inhibition of a chromatin modulator as a novel combined approach to enhance the chemotherapeutic activity of doxorubicin. They show that the application of a chromodomain inhibitor enhanced the toxicity of doxorubicin in cultured glioblastoma and breast cancer cells. This work could lead to future chemotherapeutic strategies with improved response in patients, by development of related compounds or discovery of novel drug molecules acting through epigenetic mechanisms. Ehrlich et al. use bioinformatic analyses to identify genes that are differentially expressed in skeletal muscle compared to cardiac muscle, to brain tissue, and to muscle progenitor cells in culture to probe the function of DNA hypomethylation in enhancer regions. They show that DNA hypomethylation of these enhancers correlates nicely with tissue-specific expression and speculate that this epigenetic modulation may help establish or maintain the enhancer function. In addition, they clone one of these enhancer elements into a reporter and demonstrate high levels of expression in a myoblast cell line, but not in a breast-cancer cell line, and that the expression is regulated by DNA methylation.