Modern insight into the function of chromatin began with the studies of the cytologist E. Heitz who proposed in 1928 that chromatin has certain genetic attributes. From an earlier time, cytologists had seen an odd assortment of densely stained agglomerations in the cell nuclei of various species of plants and animals. By following chromosomes through cell division cycles, Heitz could distinguish two classes of chromosomal material: euchromatin, which underwent cyclical condensation and unraveling, and heterochromatin, which maintained its compactness in the nucleus. The repressive action of chromatin on gene action had already been recognized at that time and the two chromatin states were viewed as a visible guide to gene action. Nearly 40 years later, Spencer Brown saw the investigation of chromatin as one of the most challenging and diffuse in modern biology in his first-rate review of the subject.31 Brown believed that resolution of the properties of euchromatin and heterochromatin would eventually improve our understanding of the systems controlling gene action in higher organisms.
More recent research has greatly enhanced our knowledge of the chemical nature of epigenetic modifications and gene expression.32-34 We now know in affirmation of Brown's prediction that the genomes of many animals including humans are compartmentalized into either transcriptionally competent euchroma-tin or transcriptionally silent heterochromatin. Chromatin is a polymeric complex that consists of histone and nonhistone proteins. Genomic DNA in all eukaryotic cells is packaged in a folded, constrained, and compacted manner by a several thousand-fold reduction in association with this polymer. The basic building block of chromatin is the nucleosome, which consists of approximately 146 base pairs of DNA wrapped around a histone octamer that contains two molecules each of core histones H2A, H2B, H3, and H4. These units are organized in arrays that are connected by histones of the H1 linker class. Repeating nucleosome cores are assembled into higher-order structures that are stabilized by linker DNA and histone H1.33 One of the functional consequences of chromatin packaging is to prevent access of DNA-binding transcription factors to the gene promoter. The amino termini of histones of chromatin are subject to a variety of posttranslatio-nal modifications such as acetylation, phosphorylation, methylation, ubiquina-tion, and ATP-ribosylation and as chromatin structure is plastic, the potential exists that an enormous number of combinations of these modifications could lead to activation or repression of gene expression. It is clear that chromatin remodeling is closely linked to gene expression, but the mechanism or mechanisms by which this occurs are not well understood.
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