Advances in epigenetics link genetics to the environment and disease (Nice Review)

Biologists have long sought to understand how a fertilized egg can form an organism composed of hundreds of specialized cell-types, each expressing a defined set of genes. Same with an acorn: how does this little nut form an oak tree, complete with leaves, branches, trunk and roots? Cellular identity is now accepted to be the result of the expression of specific combinations of genes. This expression pattern must be established and maintained — two distinct, but interconnected, processes. The capacity of a single fertilized egg (zygote) to establish innumerable distinct cell-types depend to a large extent on the coordinated deployment of hundreds of transcription factors that bind to specific DNA sequences which then activate, or repress, transcription of cell lineage genes.

This establishment phase corresponds most closely to what is generally cited as the first definition of epigenetics (by Conrad Waddington), namely “the study of the mechanisms by which the genotype produces the phenotype (trait) in the context of development.” The maintenance phase often involves a plethora of non-DNA sequence-specific chromatin cofactors that set up and maintain chromatin states via cell division, and — for extended periods of time — sometimes in the absence of the initial transcription factors. This phase is more akin to a definition of epigenetics (put forward by Nanney, and then elaborated on by Riggs and Holliday, and further modified by Bird and others) to mean “the inheritance of alternative chromatin states in the absence of changes in DNA sequence.”

DNA methylation was proposed, early on, as a carrier of epigenetic information — with subsequent work revealing that chromatin proteins (histones) and noncoding RNAs are also important for this process. For example, histone variants and histone modifications can influence local chromatin structure, either directly or indirectly. Such modifications can be heritable, but reversible, and are governed by a series of “writers” (that deposit the modifications), “readers” (to interpret them) and “erasers” (to remove them). Finally, higher-order 3-dimensional chromosome folding is also thought to modulate gene expression and might contribute to inheritance.

This article [see attached] reviews how the epigenetics field has evolved over the last few decades, and details some of the recent advances — that are changing our understanding of biology. Authors discuss the interplay between epigenetics and DNA sequence variation, as well as implications of epigenetics involvement in cellular memory and plasticity (especially of neurons in the nervous system). Authors also consider the effects of the environment — and both intergenerational and transgenerational epigenetic inheritance — on biology, disease and evolution (‘intergenerational’ = within the same generation; ‘transgenerational’ = the trait is ‘there’ in grandparents, parents and children). Finally, some new frontiers in epigenetics are presented, with implications for human health. 😊


Nature 25 July 2019; 571: 489-499

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