All of the above types of modifications are reversible, with one enzyme serving to create a particular type of modification, and another to remove it. These enzymes are highly specific. Thus, for example, acetyl groups are added to specific lysines by a set of different histone acetyl transferases (HATs) and removed by a set of histone deacetylase complexes (HDACs). Likewise, methyl groups are added to lysine side chains by a set of different histone methyl transferases and removed by a set of histone demethylases. Each enzyme is recruited to specific sites on the chromatin at defined times in each cell’s life history. For the most part, the initial recruitment depends on transcription regulator proteins (sometimes called “transcription factors”). As we shall explain in Chapter 7, these proteins recognize and bind to specific DNA sequences in the chromosomes. They are produced at
KEY:
Figure 4–34 The covalent modification of core histone tails. (A) The structure of the nucleosome highlighting the location of the first 30 amino acids in each of its eight N-terminal histone tails (green). These tails are unstructured and highly mobile, and thus will change their conformation depending on other bound proteins. (b) well-documented modifications of the four histone core proteins are indicated. Although only a single symbol is used here for methylation (m), each lysine (k) or arginine (R) can be methylated in several different ways. Note also that some positions (e.g., lysine 9 of H3) can be modified either by methylation or by acetylation, but not both. most of the modifications shown add a relatively small molecule onto the histone tails; the exception is ubiquitin, a 76-amino-acid protein also used for other cell processes (see Figure 3–69). Not shown are more than 20 possible modifications located in the globular core of the histones. (A, PDb: 1kX5; b, adapted from H. Santos-Rosa and
C. Caldas, Eur. J. Cancer 41:2381–2402, 2005. with permission from Elsevier.) different times and places in the life of an organism, thereby determining where and when the chromatin-modifying enzymes will act. In this way, the DNA sequence ultimately determines how histones are modified. But in at least some cases, the covalent modifications on nucleosomes can persist long after the transcription regulator proteins that first induced them have disappeared, thereby providing the cell with a memory of its developmental history. Most remarkably, as in the related phenomenon of position effect variegation discussed above, this memory can be transmitted from one cell generation to the next.
Very different patterns of covalent modification are found on different groups of nucleosomes, depending both on their exact position in the genome and on the history of the cell. The modifications of the histones are carefully controlled, and they have important consequences. The acetylation of lysines on the N-terminal tails loosens chromatin structure, in part because adding an acetyl group to lysine removes its positive charge, thereby reducing the affinity of the tails for adjacent nucleosomes. However, the most profound effects of the histone modifications lie in their ability to recruit specific other proteins to the modified stretch of chromatin. Trimethylation of one specific lysine on the histone H3 tail, for instance, attracts the heterochromatin-specific protein HP1 and contributes to the establishment and spread of heterochromatin. More generally, the recruited proteins act with the modified histones to determine how and when genes will be expressed, as well as other chromosome functions. In this way, the precise structure of each domain of chromatin governs the readout of the genetic information that it contains, and thereby the structure and function of the eukaryotic cell.
H3.3 gene expression,H2AZ chromosome segregation transcriptional repression,macroH2A X-chromosome inactivation
Chromatin Acquires Additional variety Through the Site-Specific Insertion of a Small Set of Histone variants