Edited by Brian P. Chadwick and composed of 17 chapters from thought leaders in academia and industry, this is one text you don’t want to miss. It covers a wide breadth of topics ranging from DNA methylation to Chromatin to ncRNA, with insight from across the tree of life and related human disorders. The perspective is modern from both the aspects of fundamental biology and technical breakthroughs, offering up the latest insights into the molecular players of the epigenome from the pioneering experts themselves.
The Identification of Mammalian Proteins Involved in Epigenetics
Luke Isbel, Harry Oey, and Emma Whitelaw
Non-mammalian models have yielded great insight into the fundamentals of the epigenome, as highlighted by mutagenesis screens in Drosophila and Yeast. In fact those little flies and yeast have really made their mark in our understanding of heterochromatin boundaries as exemplified by the position-effect variegation. However, these model organisms have limitations, including the fact that some gene silencing mechanisms are essentially absent, with a prime example being DNA methylation in Drosophilla. Thus, mammalian models have always been a needed driving force of our understanding of DNA methylation and related proteins.
Two types of massive screening approaches have been utilized in mammalian models: Random mutagenesis screens in mice and also RNAi in cell lines. One of the first approaches was the Agouti mouse model. It enabled study of the position-effect variegation in a mouse model and gave birth to the concept of the metastable epiallele by allowing for an examination of heritable alterations that are independent of underlying sequence. The chapter then goes into the details of a screening technique known as Modifiers of Murine Metastable Epialleles and all the systematic insight it provided into epigenetic proteins (both known and unknown). After going into the history of screening for epigenetic proteins the authors then provide state of the art coverage of screening techniques and highlight the next challenge of putting the puzzle together to figure out how all these proteins interact.
Epigenetic Mechanisms in Rett Syndrome
Rett syndrome (RTT) is a neurodevelopmental disorder that affects 1 in 10 000 people. It has many similarities to Autism Spectrum Disorders (ASDs) but it also happens to have one distinct difference, the molecular cause is known. RTT is caused by mutations to Methyl CpG Binding Protein 2 (MECP2). Interestingly, the nature of MeCP2 means RTT is an epigenetic disease at two levels. First, RTT has a strong gender bias, which is because it is an X-linked gene. Thus, due to the relatively stochastic nature of X-inactivation, the affected females are mosaics of wild-type and mutated MeCP2. However, a pattern of inheritance and expression related to X-inactivation isn’t always the case. Second, MECP2 encodes a methyl binding domain (MBD), which is a classic reader of the methylome. But the complexities of MeCP2 don’t end there as it wears many masks. MECP2 has multiple isoforms, undergoes extensive post-translational modification, can bind RNA and unmethylated DNA, and likes to party with quite a few co-factors that give this disordered protein some much needed structure. All of this diversity allows it to take on different functions depending on tissue and developmental stage. Thus, while originally thought to be a transcriptional repressor, MECP2 has emerged as a context dependent regulator of the epigenome that acts more like a histone mod than generic transcriptional repressor, as it can have long-range interaction with active genes at their CpG shores. By digging deeper into these functional molecular mechanisms and putting together the complex interactions we can begin to understand how the epigenome is read, how RTT progresses, and finally begin to develop effective therapies.
Environment and the Epigenetic Transgenerational Inheritance of Disease
Ingrid Sadler-Riggleman and Michael K. Skinner
Transgenerational inheritance is one of epigenetics’ hottest topics and explains a large chunk of modern disease. It all started with Skinner’s work on endocrine disruptors used as fungicides and pesticides on common crops. Since then the field has exploded and found the effects from other common chemicals like more pesticides, plastic, and jet fuel.
This chapter dives deep into non-Mendelian inheritance and starts with Skinner’s work as well as the Agouti mouse model. It then offers comprehensive coverage of the environmental toxicants capable of inducing transgenerational effects including Vinclozolin, Methoxychlor, DEET, Dioxin, BPA, Phthalates, and Tributlyin. The chapter doesn’t just end there as they also examine other exposures including caloric restriction, high fat diets, stress, folate, drought, heat/salt stress, prediabetes, smoking, and alcohol consumption. Next, the chapter examines the molecular and evolutionary mechanisms behind alterations to the germ-line, which result in somatic-lines that exhibit different impacts from the same exposure. This chapter then ties into the next by Jaclyn M. Goodrich and Dana C. Dolinoy, which covers exposures from a public health perspective and offers up insight into other common exposures including metals (Mercury, Cadmium, and Lead) and persistent organic pollutants, like polychlorinated biphenyls (PCBs).
Read On Friends
Check out the list of topics/authors, and maybe even grab a copy of Epigenetics: Current Research and Emerging Trends at the Horizon Press website. Also be sure to check out our coverage of the earlier related texts: Epigenetics: A Reference Manual and Epigenetics.
**EpiGenie would like to thank Ben Laufer from the Singh Lab at the University of Western Ontario for the contributing this book summary**