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nucleosome

Tuesday 16 September 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).

These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modifications.

Enzymes involved in this process include DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone acetylases, histone methyltransferases and the methyl-binding domain protein MECP2.

Alterations in these normal epigenetic patterns can deregulate patterns of gene expression, which results in profound and diverse clinical outcomes.

Structure

The basic repeat element of chromatin is the nucleosome. The nucleosome consists of a central protein complex, the histone octamer, and 1.7 turns of DNA, about 146 base pairs, which are wrapped around the histone octamer complex.

There are four different types of core histone proteins which form the octamer containing two copies each of H2A, H2B, H3 and H4. Further, there is a linker histone, H1, which contacts the exit/entry of the DNA strand on the nucleosome.

The nucleosome together with histone H1 is called a chromatosome.

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.

Nucleosome remodeling

Assembly, mobilization and disassembly of nucleosomes can influence the regulation of gene expression and other processes that act on eukaryotic DNA.

Distinct nucleosome-assembly pathways deposit dimeric subunits behind the replication fork or at sites of active processes that mobilize pre-existing nucleosomes. Replication-coupled nucleosome assembly appears to be the default process that maintains silent chromatin, counteracted by active processes that destabilize nucleosomes.

Nucleosome stability is regulated by the combined effects of nucleosome-positioning sequences, histone chaperones, ATP-dependent nucleosome remodellers, post-translational modifications and histone variants.

Histone turnover helps to maintain continuous access to sequence-specific DNA-binding proteins that regulate epigenetic inheritance, providing a dynamic alternative to histone-marking models for the propagation of active chromatin.

Nucleosome remodeling complexes modify chromatin topology in an ATP-dependent manner by disrupting DNA-histone interactions. They thereby facilitating sliding of the nucleosome, and hence the accessibility of the DNA to transcription factors.

The SWI/SNF complex regulates genes locally, and analyses of yeast SWI/SNF mutants revealed that transcription of 5% of all yeast genes is influenced by SWI/SNF mutations.

The SWI/SNF core complex consists of SNF5/INI1, BRG1, BRM, BAF155, and BAF170. SWI/SNF interacts with many protein complexes central to cancer development, such as RB, p53, MYC, MLL, BRCA1, and beta-catenin; hence, functional inactivation of SWI/SNF impinges on a multitude of cellular growth control pathways.

Analyses of the SWI/SNF core subunit SNF5 (INI1) have revealed the presence of inactivating mutations in highly aggressive human malignant rhabdoid tumors. SNF5 mutations are underlying familial cancers in which one SNF5 allele carries a germ-line mutation and the other allele is lost during tumorigenesis.

The tumor-suppressive effect of SNF5 is evident from the fact that reintroduction of SNF5 into SNF5-mutant tumor cells mediates cell cycle arrest and from mouse models demonstrating Snf5 as a haploinsufficient tumor-suppressor gene, complete loss of which causes mice to succumb early in life to aggressive lymphomas or rhabdoid tumors.

BRM and BRG1

BRM and BRG1 are ATPase core subunits of the mammalian SWI/SNF complex. The two proteins are 75% similar in protein composition, are mutually exclusive in chromatin remodeling complexes in vitro (Phelan et al. 1999), and appear to have tumor-suppressor functions.

BRG1 has been found mutated in cell lines from lung, pancreas, prostate, and breast cancers (Wong et al. 2000; Decristofaro et al. 2001).

BRG1/BRM expression was found lost in 10% of primary lung tumors correlating with a poor prognostic outcome (Reisman et al. 2003).

Whereas Brg1-deficiency causes early embryonic lethality in mice, Brg1+/- animals are prone to epithelial tumors, possibly due to haploinsufficiency for Brg1 in tumor suppression, as the outgrowing tumors retained the remaining wild-type Brg1 allele (Bultman et al. 2000).

Brm-deficient mice are viable, likely via adaptive upregulation of Brg1 (Reyes et al. 1998).

Although Brm-/- mice do not appear tumor prone, the mice are larger than wild type, and isolated mutant fibroblast cells display G0/G1 checkpoint failure on DNA damage, indicating a role for BRM in cell cycle regulation (Reyes et al. 1998).

As BRM was originally identified in Drosophila as a suppressor of Polycomb (Tamkun et al. 1992), it is tempting to speculate that loss of BRM or BRG1 impinge on cellular homeostasis by affecting the balance between TrxG and PcG protein complexes.

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