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From the moment of conception, orchestrated epigenomic changes allow for proper development of the embryo, as well as establishment of the fetal germline (and hence the subsequent generation). The organization of the sperm and egg genomes undergo rapid epigenetic remodeling, primarily in waves of methylation and demethylation, in order to assure zygote viability (Fig. 172-1). As the cell readies for its first division, these early epigenomic modifications help to ensure proper condensation of the DNA, its packaging into chromatin, and proper division of the chromosomes between subsequent cells.

Figure 172-1

The embryonic methylome is erased and reestablished in utero. Upon fertilization, the paternal genome goes through a rapid round of active demethylation. The maternal genome is also demethylated, but in a passive process involving DNA replication without rounds of active re-methylation. As the fetus develops, DNA methylation patterns are reestablished in the embryonic tissues. The extraembryonic tissues, including the placenta, remain largely hypomethylated.

The first differentiation event in human development occurs when embryonic stem cells (ESCs) differentiate to become trophoblast stem cells. These cells form the trophectoderm of the blastocyst. This differentiation event is essential, as the trophectoderm gives rise to the extraembryonic tissues required to support the pregnancy, including the placenta. However, the ESCs and the trophectoderm all have the same genetic information. This begs the question, what drives transcriptional activation and silencing along distinct lines in these 2 cells types? As development proceeds, how can cells that have the exact same genetic material eventually become hepatocytes or neurons, expressing vastly different proteins and having completely different functions?

The answer lies in the understanding of gene regulation, which inherently incorporates epigenomics (Fig. 172-2). Epigenetic modifications function to repress or activate genes, organize chromatin structure, and repair damaged DNA. These modifications enable maintenance of cellular memory of previous gene activation events and ensure genome stability. Similar to the underlying DNA backbone, epigenetic modifications are “heritable” during the cell cycle. Throughout the process of DNA replication, the DNA becomes accessible to the replication machinery. Following behind the replication machinery, chromatin remodeling enzymes are at play, reestablishing the chromatin structure to its previous state. When the cell divides, the chromatin state of each cell is seemingly identical.

Figure 172-2

Epigenetics: heritable information beyond the DNA sequence. Epigenetic modifiers aid in stable alterations of gene expression. Such modifiers include changes in DNA methylation, posttranslational histone modifications, and noncoding RNAs.

While mechanisms enable genomic DNA heritability with limited nucleotide variation across many generations, the mechanisms regulating heritability of the epigenome are an area of intense investigation. In essence, the epigenome must allow for generation-to-generation stability, yet enable dynamic plasticity and responsiveness to a varying intrauterine environment. As ...

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