Tfiid

(TATA binding protein)

Regulatory region

Activator protein

Regulator protein

Regulator protein

I P0

■ Figure 2-13 Interaction of transcription factors and nucleosome acetylation at the regulatory region of a gene (top) induce assembly of protein factors and RNA polymerase at the promoter (bottom).

The involvement of histone modification with gene expression has led to the study of aberrations in these modifications in disease states such as viral infections and neoplastic cells. Thus, analysis of histone states may be another target for diagnostic, prognostic, and therapeutic applications.

Advanced Concepts

One theory holds that pre-existing and gene-specific histone modifications constitute a histone code that extends the information potential of the genetic code.67 Accordingly, euchromatin, which is tran-scriptionally active, has more acetylated histones and less methylated histones than transcriptionally silent heterochromatin made up of more condensed nucleosome fibers. Although methylated histones can activate transcription by recruiting histone acety-lases, establishment of localized areas of histone methylation can also prevent transcription by recruiting proteins for heterochromatin formation and is one form of gene or transcriptional silencing.68 Transcriptional silencing is responsible for inactiva-tion of the human X chromosome in female embryo development and position effects, the silencing of genes when placed in heterochromatic areas.

Nucleosome

Nucleosome

■ Deacetylation and methylation of histones can establish silenced regions of DNA.

DNA Modification

DNA methylation is another type of epigenetic regulation of gene expression in eukaryotes and prokaryotes. In vertebrates, methylation occurs in cytosine-guanine—rich sequences in the DNA (CpG islands) (Fig. 2-14). CpG islands were initially defined as regions >200 bp in length with an observed/expected ratio of the occurrence of CpG >0.6.36 This definition may be modified to a more selective GC content to exclude unrelated regions of naturally high GC content.37 CpG islands are found around the first exons, promoter regions, and sometimes toward the 3' ends of genes. Aberrant DNA methylation at these sites is a source of dysregulation of genes in disease states. Methylation of cytosine residues in the promoter regions of tumor suppressor genes is a mechanism of inactivation of these genes in cancer.38 Methods to analyze promoter methylation have been developed.39,40 Methylation of DNA is the main mechanism of genomic imprinting, the gamete-specific silencing of genes.41,42 Imprinting maintains the balanced expression of genes in growth and embryonic development by selective methylation of homologous genes. This controlled methylation occurs during gametogenesis and is different in male and female gametes. A convenient illustration of imprinting is the comparison of mules and hinnies. A mule (progeny of a female horse and male donkey) has a distinct phenotype from that of a hinny (progeny of a male horse and a female donkey). The difference is due to distinct imprinting of genes inherited through the egg versus those inherited through the sperm. Genetic diseases in humans, Angelman's syndrome and Prader-Willi syndrome, are clinically distinct conditions that result from the same genetic defect on chromosome 15. The phenotypic differences depend on whether the genetic lesion involves the maternally or paternally inherited chromosome. Imprinting may be partly responsible for abnormal development and phenotypic characteristics of

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