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Key Points

  • Epigenetics refers to heritable mechanisms that influence the activity of DNA but do not include the DNA sequence itself.

  • Despite being a relatively young field, epigenetics has provided critical insights into gene regulation and addressed important gaps in our understanding of how static DNA sequence is normally interpreted in a dynamic fashion, both temporally and spatially.

  • Imprinting disorders and cancer are examples of germline and somatic epigenetic disorders, respectively. In addition, there is a growing appreciation of epigenetic consequences of a number of “single” gene disorders such as fragile-X syndrome, Immunodeficiency, centromeric instability and facial anomalies (ICF), and Rett syndrome.

  • The demonstration that the epigenetic signature of a given cell can be completely reversed to the level of pluripotency is the ultimate proof of the plasticity of the epigenome and its candidacy for therapeutic intervention to treat epigenetic disorders and make inroads in regenerative medicine.


The phenomenon of marked phenotypic and functional differences between the different cell types of the human body presents a major challenge in the field of biology. If DNA truly functions as the “operation manual,” how do cells that share the same copy of the manual act so differently? Indeed, the initial enthusiasm in decoding this manual through the Human Genome Project has inadvertently fueled the perception, especially among nongeneticists, that deciphering the DNA sequence is the ultimate answer to biologic diversity. However, the remarkable progress made in this regard left many questions unanswered and only emphasized that DNA sequence represents only the most basic level of analysis of the human genome and that higher-order organization is key to its proper function, much like how the amino acid sequence of a protein is only meaningful in the context of its tertiary structure. The term “epigenetics” describes mechanisms that influence the activity of DNA that do not include the DNA sequence itself. While the original use of the term was more vague and inclusive of environmental factors, the term is nowadays limited to heritable molecular mechanisms although environmental factors are increasingly recognized as major modulators of these molecular mechanisms. More specifically, the “epigenome” refers to the constellation of covalent modifications of DNA and the histone proteins that help pack DNA on the chromosome as well as the newly discovered noncoding transcripts that function to modulate the transcriptional activity of DNA. So while the first-order organization of DNA (ie, DNA sequence) is essentially the same in all cells of the human body, the context in which the sequence occurs varies greatly, conferring tissue-specific “epigenomes” that in turn determine the transcriptional signature of a cell (transcriptome) as well as the profile of proteins it produces (proteome).

Despite its relatively young age, the field of epigenome has provided invaluable insight into the transcriptional regulation of DNA and the pathogenesis of several rare and common disorders. This chapter will summarize our current understanding of the epigenetic mechanisms, how they ...

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