Wednesday 16 July 2003
The human genome contains 23 000 genes that must be expressed in specific cells at precise times. Cells manage gene expression by wrapping DNA around clusters (octamers) of globular histone proteins to form nucleosomes.
These nucleosomes of DNA and histones are organized into chromatin. Changes to the structure of chromatin influence gene expression: genes are inactivated (switched off) when the chromatin is condensed (silent), and they are expressed (switched on) when chromatin is open (active).
Alterations in these normal epigenetic patterns can deregulate patterns of gene expression, which results in profound and diverse clinical outcomes.
Two each of the core histones (H2A, H2B, H3, and H4) form an octamer, as the protein moiety of the core structure of the nucleosome. The linker histone H1 is involved in sealing 2 rounds of nucleosome DNA at the surface of the nucleosome core and is also involved in the formation of higher order structures of chromatin.
Because of their function in organizing chromosomal structure, histones contribute to virtually all chromosomal processes, such as gene regulation, chromosome condensation, recombination, and replication.
Each class of histone proteins, except H4, consists of several subtypes that are encoded by different genes.
In mammals, these genes can be divided with respect to their expression, into 3 major groups:
(1) replication-dependent histone genes, whose expression is restricted to the S phase of the cell cycle;
(2) replication-independent histone genes, which encode the so-called replacement histones, expressed at a low but constant level throughout the cell cycle and in nondividing differentiated cells
(3) genes encoding tissue-specific isotypes, such as the exclusively testicularly expressed H1T (MIM.142712) and H3T (MIM.602820) genes.
The genes for the replacement variants show solitary locations within the genome, and some of these are interrupted by introns, whereas the other histone genes are intronless and are organized in clusters.
Nucleosomes and histone proteins
Epigenetic gene regulation has the nucleosome on center stage. The nucleosome is made up of approximately two turns of DNA wrapped around a histone octamer built from two subunits of each histone, H2A, H2B, H3, and H4, respectively, In between core nucleosomes, the linker histone H1 attaches and facilitates further compaction.
Aside from the core histones, a variety of variant histone proteins exist and can be inserted into the nucleosome, possibly serving as landmarks for specific cellular functions.
The N-terminal tails of the histone proteins are protruding out from the nucleosomal core particles, and these tails serve as regulatory registers onto which epigenetic signals can be written.
Covalent modification of histones includes acetylation of lysines, methylation of lysines and arginines, phosphorylations of serines and threonines, ADP-ribosylation of glutamic acids, and ubiquitination and sumolyation of lysine residues.
The pattern of histone modifications signifies the status of the chromatin locally and has been coined the histone code.
A second group of proteins, containing bromodomain and chromodomain modules, use the epigenetic marks on the histone tails as recognition landmarks to bind the chromatin and initiate downstream biological processes such as chromatin compaction, transcriptional regulation, or DNA repair.
Although histone acetylation in general correlates with transcriptional activity, histone methylations can serve as anchorage points for both activator and repressor complexes and are thereby involved in conferring an epigenetic inheritance to the cell, carrying information related to differentiation commitment and function.
Although most histone modifications are reversible, no histone demethylase has been identified as yet, suggesting histone methylation to be involved in processes of long-term regulation.
histone proteins (H1s, H2s, H3s, H4s, H5s)
histone modifying enzymes
- histone methyltransferases
- histone acetyltransferases
- histone deacetylases
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Iizuka M, Smith MM. Functional consequences of histone modifications. Curr Opin Genet Dev. 2003 Apr;13(2):154-60. PMID: 12672492
Lehrmann H, Pritchard LL, Harel-Bellan A. Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation. Adv Cancer Res. 2002;86:41-65. PMID: 12374280