Primer in Genetics and Genomics, Article 6: Basics of Epigenetic Control

Abstract

The epigenome is a collection of chemical compounds that attach to and overlay the DNA sequence to direct gene expression. Epigenetic marks do not alter DNA sequence but instead allow or silence gene activity and the subsequent production of proteins that guide the growth and development of an organism, direct and maintain cell identity, and allow for the production of primordial germ cells (PGCs; ova and spermatozoa). The three main epigenetic marks are (1) histone modification, (2) DNA methylation, and (3) noncoding RNA, and each works in a different way to regulate gene expression. This article reviews these concepts and discusses their role in normal functions such as X-chromosome inactivation, epigenetic reprogramming during embryonic development and PGC production, and the clinical example of the imprinting disorders Angelman and Prader-Willi syndromes.

Keywords: DNA methylation; X-chromosome inactivation; chromatin; epigenomics; histone code.

Figure 1.

Chromatin. DNA coils around histones to form nucleosomes (blue circles wrapped with two coils). Euchromatin is “active” since it is less compacted and available for transcription. Heterochromatin is “silent” since it is tightly compacted and not accessible for transcription. Note how the nucleosomes appear as “beads on a string.” This figure is reproduced from an open-access article (Sha & Boyer, 2009) distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/3.0/

Figure 2.

(A) Schematic of epigenetic modifications. Strands of DNA are wrapped around histone octamers, forming nucleosomes. These nucleosomes are organized into chromatin, the building blocks of a chromosome. Reversible and site-specific histone modifications occur at multiple sites through acetylation, methylation, and phosphorylation. DNA methylation occurs at five-position of cytosine residues in a reaction catalyzed by DNA methyltransferases. Together, these modifications provide a unique epigenetic signature that regulates chromatin organization and gene expression. (B) Schematic of the reversible changes in chromatin organization that influence gene expression. Genes are expressed (switched on) when the chromatin is open (active), and they are inactivated (switched off) when the chromatin is condensed (silent). White circles = unmethylated cytosines (these are the circles in the “transcription possible” diagram); red circles = methylated cytosines (these are the circles in the “transcription impeded” diagram). Reprinted, with permission, from Rodenhiser and Mann, (2006), under license from Access Copyright. Further reproduction, distribution, or transmission is prohibited except as otherwise permitted by law.

Figure 3.

CpG islands on the promoter region of the gene. When these islands are methylated, gene expression is repressed. Reproduced from http://missinglink.ucsf.edu/lm/genes_and_genomes/methylation.html courtesy of Benjamin Huang, MD, University of California San Francisco.

Figure 4.

DNA methylation reprogramming in the mammalian life cycle. In the zygote, DNA from the paternal gamete is rapidly, actively demethylated by TET protein, while passive demethylation of the maternal gamete occurs more slowly through the lack of DNMT1 activity. DPC = days postconception; ICM = inner cell mass; PGC = primordial germ cell; DNMT = DNA methyltransferase. Adapted from Seisenberger et al. (2013), licensed under CC BY 3.0.