After working on some of the UK’s first embryonic stem cells and developing the world’s first cloned human embryos, Lyle Armstrong turned his attention to the creation of a useful text that would benefit the epigenetic novice as well as the seasoned investigator. With a number of groovy figures and illustrations, they key concepts of Epigenetics are explained in a simple and concise manner, and through some sorcery the text also manages to hit a number of frontiers in the field. That’s pretty impressive for this lean and mean book, which comes in at just under 300 pages. Here’s a quick primer of one of the chapters:
Epigenetic Predisposition to Disease
The first thirteen chapters were dedicated to showing how epigenetics acts as “a versatile mechanism by which the information content of the genome can be used in a selective manner to define cellular phenotypes and respond to environmental influences that cells experience during their lives“, the focus switches onto how perturbations to these mechanisms can cause long-term changes that alter physiology into the state known as disease. Interestingly, it appears that due to modern advances the most devastating diseases have now shifted from being caused by external events (such as pathogens) to being caused by internal problems that create a predisposition, but not guarantee, to develop a disease. And so it has become evident that epigenetic mechanisms are the basis for stochastic variation in complex disease and may just give epidemiology and GWAS the helping hand they needs to decipher all the ‘environmental’ factors contributing to complex “internal attacks”.
Genomic Imprinting is a classic epigenetic topic because of its unusual role in creating uni-parental gene expression for establishing complex traits and it’s apparent environmental sensitivity. And this section serves as a great primer, by examining how imprinting disorders can persist beyond embryogenesis. Using the example of the classic sister imprinting disorders, Prader-Willi and Angelman Syndromes, the functional consequences of changes to imprinted clusters of genes and ncRNA highlight how these perturbations can change brain development and function. However, the case for imprinting diseases doesn’t end there as next up are the sister disorders of the IGF-H19 locus: Beckwith-Wiedemann and Silver-Russell Syndromes.
Major Disease Groups
Next, the chapter goes on to examine the epigenetic mechanisms that hold predictive value for diseases with complex multifactorial causes. Interestingly, it appears that seemingly distinct diseases share some “mechanistic threads” that include epigenetic alterations to the homeostatic systems that maintain blood flow, fluid/electrolyte balance, and glucose metabolism. For example, the text examines the epigenetic causes of atherosclerosis that underlie cardiovascular disease, while also touching on a number of other heart conditions, and suggesting that epigenetic drift may be an contributor. The chapter is then wrapped up with some examples from Kidney Disease and Diabetes.
**Chapter Summary provided by Ben Laufer, PhD student at Western University**
Methylation Regulation at Specific Gene Loci
Chapter 5.5 discusses the continually evolving area of epigenetic research involving methylation regulation at specific gene loci. Noting that the field is still quite fluid, here are some conclusions that can be drawn at this point:
- DNA methylation is working in concert with histone biochemistry, with specific post-translational modification of histones exposing or protecting gene promoters from DNA methyltransferases.
- Transcription factors may regulate gene expression through direct or indirect, histone-mediated interaction with DNA methyltransferases, which seem to be unaffected by the interaction with other types of proteins.
- Epigenetic control of miRNAs might be achieved through methylation of the CpG islands found in the proximity of their coding regions or indirectly by methylating the promoters of transcription factors involved in their regulation. However, there is a bidirectional effect, with miRNAs also having post-transcriptional effects on DNA methyltransferases and their recruiting DNA binding factors.
- Increasing evidence shows that noncoding RNAs can bind chromatin modifying enzymes directly or interact with specific sites of the DNMT1, 3A and 3B genes, thus acting through alternative mechanisms as important epigenetic controllers.
- The epigenetic regulation of gene expression is based upon a concerted interaction of specialized enzymes, transcription factors and miRNAs which coexist in a reciprocal, self-regulating system.
**Chapter Summary contributed by Daniel Lupu, Graduate Research Assistant at the University of North Carolina**
Epigenetics of Cancer
In Ch.16, Armstrong provides readers with a grounded and sufficient description of the major well-characterized molecular and genetic events in typical cancers to allow for a tack in the discussion to a focus on epigenetic influences in cancer.
The chapter provides a balance of discussion between DNA methylation changes involved in cancer and the less-well studied area of histone modifiers with confirmed or suspected ties to cancer. The chapter finishes with a section to thread the reader’s learning from the chapter with specific examples of cancer that are tied to problems in epigenetic regulation.
These are some of the major take away points from the chapter:
- Tissue homeostasis – a balance of normal cell turnover to maintain normal tissue size and function – is lost with disruption of normal cell regulation mechanisms, and this can lead to cancer.
- Changes in expression or mutation of key genes that control cell division, lead to cell transformation.
- Epigenetic changes can also result in aberrant expression of tumor suppressors or oncogenes can tip a cell out of growth control towards cancer. These changes can include changes in methylation states at specific genes that are known or potential tumor suppressors or oncogenes, or they can occur at the level of the histones, the regulation of which is key to making a region of DNA accessible or blocked from transcription.
- Examples of epigenetic dysregulation that lead to cancer include methylation changes in HOX gene clusters as critical players in hematological malignancies and inactivation by DNA methylation of tumor suppression genes in lung cancers.
The understanding of basic epigenetics is certain to grow in leaps and bounds in the coming years with the advent of new tools, technologies and hypotheses that can be applied to the field of epigenetics. The growth in our understanding of the epigenetics of cancer is certain to parallel, and at times leap-frog, basic epigenetics biology in the coming years. However, Armstrong’s text provides readers a grounded introduction to the relevant topics before they seek more specialize reviews on their chosen sub-topic.
**Chapter Summary provided by Dr. Bruce Adams, Scientist at Quanticel Pharmaceuticals**
The EpiGenie Verdict
Epigenetics doesn’t go into excruciating detail, and that’s a good thing. It surveys the entire breadth of the field of epigenetics, and through it’s clever use of diagrams and figures, is able to clearly and simply convey the concepts that form the basis for today’s cutting edge research. Epigenetics by Lyle Armstrong is a great resource for grad students and researchers alike.
You can get a copy of Epigenetics at the Garland Science website