There has never been, in my opinion, a more expansive time in the history of biological studies. The sequencing of hundreds of organismal genomes coupled with the latest “omics” approaches have opened up new vistas that have revolutionized our view of biology. Nowhere is this more apparent than in the field of gene regulation, where a host of newly discovered mechanisms are now known to control where and when genes are turned on and off, and how these regulatory states are passed from one generation to the next. In many cases, the information potential of DNA is controlled by protein molecules that set up and lock in repressive or active regions of the genome. Increasingly, these regulatory mechanisms and complexes are being found to involve RNAs, including long non-coding RNAs (lncRNAs) and short non-coding RNAs (e.g., microRNAs and piRNAs). Knowledge of their involvement increases our view of the complexity of gene regulation but also opens some new opportunities for harnessing this newly discovered mechanism for useful purposes, for example, in medicine.
Not only have microRNAs and other non-coding RNAs recently emerged as key regulators of gene expression during development, but they are also frequently mis-expressed in human disease states. Non-coding RNAs are increasingly being found to have causal roles in disease (e.g., in cancer, they have the ability to behave like oncogenes or tumor suppressors). These RNAs act to promote or repress cell proliferation, differentiation and death, homeostasis, and migration during development, all processes that go wrong in disease. Their molecular properties (and in some cases small size) make non-coding RNAs amenable as targets and therapeutics in disease treatment using standard antisense technologies. Non-coding RNAs thus provide the physician with a potentially powerful new battery of agents to diagnose and treat disease. However, while hundreds of human microRNAs and non-coding RNAs are known, relatively little is known about their roles, mechanisms and targets. We consider it extremely timely to dedicate an entire issue of Epigenetics to the topic of non-coding RNAs in epigenetics, with 12 reviews and 7 original research papers from prominent experts in the field to enjoy. Here is a preview of what you will find in this issue.
A series of 6 reviews nicely outlines the links between non-coding RNAs and epigenetic changes to chromatin. Peschansky and Wahlestedt (p. 3) describe the classification of long and short non-coding RNAs and their interactions with proteins in the epigenetic complexes. Roberts et al. (p.13) discuss the emerging models in which lncRNAs act to guide chromatin-remodeling complexes to specific chromatin loci or act as scaffolds to coordinate the activities of multiple proteins. Case in point, Marchese and Huarte (p. 21) discuss the roles of lncRNAs in coordinating the 3D structure of the genome and its alteration by chromatin modifiers. Jiao and Slack (p. 27) discuss the recent literature on the roles of non-coding RNAs to activate gene expression. Lastly, 2 papers discuss in detail the roles of small RNAs in epigentically contoling gene expression. Guérin et al. (p. 37) discuss the links between small RNAs and chromatin remodeling in C. elegans, and the theme is continued by Li (p. 45),who discusses these similar phenomena in mammalian cells.
Transposition is a major source of genome instability and is actively suppressed in most germline cells. Bierhoff et al. (p. 53) discuss the roles of non-coding RNAs in establishing repressive chromatin states at transposon and repetitive loci, while Kasper et al. (p. 62) describe the role of piRNAs in transposon repression in the germline of C. elegans. The importance of the piRNA machinery in normal germ cell function is illustrated in a new report from Ferreira et al. (p. 113) in which the authors find that the genes required for piRNA function are epigenetically modified in testicular cancer, leading to lower piRNA expression and loss of repression of repetitive regions. A second new paper in this area from Chen et al. (p. 119) describes the loss of a specific miRNA in testicular cancer that leads to increased DNA methylation. Staying with the cancer theme, Ferraro et al. (p. 129) show in new work that miR-21 is epigenetically regulated in colon cancer and controls genes involved in the epithelial to mesenchymal transition and metastasis. Maia et al. (p. 75) nicely review the roles of non-coding RNAs and epigenetics in various cancers with an eye to novel therapeutic uses.
There is a close link between development and disease. Few non-communicable diseases fail to benefit from a deeper understanding of the underlying biology and development of the organs or tissue involved in the disease. Buckberry et al. (p. 81) review the current state of understanding regarding the role of non-coding RNA, including miRNAs, in the development of the placenta and placental disease. Along those same lines, Doridot et al. (p. 142) describe a new role for one microRNA, miR-34 in preeclampsia, a disorder of the placenta. Continuing the theme of non-coding RNAs in development, Lopez-Ramirez and Nicoli (p. 90) review the interplay between epigenetics and miRNAs during embryonic and adult neurogenesis, while Monteleone et al. (p. 152) provide a novel example of epigenetic and microRNA control of fetal brain development and adult brain functions, in particular influenced by stress. Mathiyalagan et al. (p. 101) discuss a novel role for chromatin-associated non-coding RNAs in cardiovascular developmental programs and Zawada et al. (p. 161) reveal in new work, a link between microRNAs expressed in chronic kidney disease patients and their risk of cardiovascular disease. Arriaga-Canon et al. (p. 173) describe a new lncRNA that is important for the switching from embryonic to adult α-globin gene expression by altering active chromatin structure during development.
Clearly, knowledge in this subject area is not saturated and much remains to be discovered. Some common themes are emerging, but there are also clear differences in mechanism of action, which are waiting to be explored and exploited. While there is still a limited literature on using non-coding molecules in the clinic, the prospects for a revolution in medicinal applications are looking up.