See also Chromosomes and DNA Methylation and deMethylation and role of Epigenetic Modifications in Driving Th1/Th2 Development and Fetal Assays based on Chomatin epitopes and Histone aceylation (right hand panel). 

A large number of covalent modifications of histones have been documented, including acetylation, phosphorylation, methylation, ubiquitination, and ADP ribosylation, that take place on the amino terminus “tail” domains of histones. Such diversity in the types of modifications and the remarkable specificity for residues undergoing these modifications suggest a complex hierarchy of order and combinatorial function that remains unclear. Of the covalent modifications known to take place on histone amino-termini, acetylation is perhaps the best studied and appreciated. Recent studies have identified previously characterized coactivators and corepressors that acetylate or deacetylate, respectively, specific lysine residues in histones in response to their recruitment to target promoters in chromatin. These studies provide compelling evidence that chromatin remodeling plays a fundamental role in the regulation of transcription from nucleosomal templates.

Epigenetics is the study of heritable changes in gene expression or cellular phenotype which do not involve changes in the underlying DNA sequence itself. Epigenetic modifications do not change the DNA sequence itself but alter the transcriptional activity of genes, changing the repertoire of genes expressed by the cell. The two major epigenetic mechanisms are DNA methylation at CpG islands in the promoter and histone acetylation (see below). Methylation at CpG island silences gene transcription in most instances, but, rarely, it results in activation. Similarly, deacetylation of histones is thought to result in transcriptional silencing because of the condenstation of chromatin. Recent evidence suggests that the two processes are related. Methylated DNA appears to preferentially associate with histone deaceylase protein complexes and histone methylases. Histone methylation has been shown to result in DNA methylation. 

The chromatin in the nucleus of eukaryotic cells is regulated to permit or exclude access of the enzymatic machinery for processes such as transcription and recombination. Specific regulatory sequences in the DNA are ultimately responsible for this regulation, serving as binding sites for proteins or protein complexes that recruit specific chromatin-modifying activities. In the case of transcriptional regulation, specific DNA-bindng activators or repressors recruit histone-modifying enzymes and nucleosome remodeling complexes, generating localized modifications of the chromatin that govern the access of the transcription machinery. In addition to such localized chromatin modificaitons, there are developmentally regulated large-scale reorganizations of chromatin structure into active and inactive domains.

The amino-terminal (NH2) terminal tails of histones H3 and H4 protrude from nucleosomes and are subject to diverse modifications, including phosphorylation, methylation and acetylation. For instance, methylation of Lys 9 of histone H3 (K9/H3) is involved in the formation of stable repressive heterochromatin whereas methylation of K4/H3 is associated with transcriptional activity. These covalent modifications may alter the interaction of histone tails with DNA or serve as docking sites for chromatin associated proteins. Such modifications can loosen up or further condense chromatin or such post translational modifications can create recognition (binding) sites for other proteins that regulate gene expression. In this last process, deposition of a given modification on the histone tail is thought to specify a code that dictates the regulatory features of a gene (the “histone code” hypothesis). 

Core histone actylation is a reversible post-translational modification, and transcriptional activators and repressors recruit histone acetyltransferases (HATs) and histone deacetylases (HDACs) to gene promoters and enhancers. Chromatin remodeling and histone acetylation at regulatory regions of IL4 and IFNG is also associated with T cell differentiation. Mechanisms and examples of such chromatin alteration are as follows:

Chromatin remodeling complexes which are protein machines that use ATP hydrolysis can also change the structure of nucleosomes temporarily so that DNA becomes less tightly bound to the histone core.