Wednesday 29 October 2003
The initiation of cellular differentiation involves alterations in gene expression that depend on chromatin changes, at the level of both higher-order structures and individual genes. Chromatin-remodelling enzymes have key roles in differentiation and development.
SWI/SNF chromatin remodeling ATPases (SWI/SNF complex) control accessibility of the information stored in the genome. However, the in vivo role of these remodelers has remained poorly understood because null mutations in these result in embryonic lethality in most organisms.
The condensation of DNA into an ordered chromatin structure allows the cell to solve the topological problems associated with storing huge molecules of chromosomal DNA within the nucleus.
DNA is packaged into chromatin in orderly repeating protein-DNA complexes called nucleosomes. Each nucleosome consists of approximately 146bp of dsDNA (double-stranded DNA) wound 1.8 times around a histone octamer.
Two molecules each of H2A, H2B, H3, and H4 comprise the histone ramp around which the DNA superhelix winds. Stretches of DNA upto 100bp separate adjacent nucleosomes.
Multiple nuclear proteins bind to this linker region, some of which may be responsible for the ordered wrapping of strings of nucleosomes into higher-order chromatin structures.
Chromatin remodeling factors comprise an ATPase subunit along with other polypeptides that are responsible for the regulation, efficiency, and functional specificity of each complex.
The ATPase subunit belongs to the Snf2 (Sucrose Nonfermenting in Yeast) super family of proteins, which includes the SWI/SNF complex and the imitation SWI (ISWI) group.
The SWI2/Snf2 group includes yeast SWI/Snf (ySWI/Snf), yeast RSC, the Drosophila Brm (Brahma) complex, and the hBrm (human Brm) and SMARCA4 (BRG1) (Brm/SWI2 Related Gene-1, hBRG1 in humans) complexes.
Moreover, there are many other proteins that are closely related to the ATPase subunits of chromatin remodeling complexes. In order to remodel chromatin, remodeling complexes recognize and bind to their substrate.
The SWI/Snf, NURF, and RSC complexes act as ATP-dependent motors that track along the DNA strands and pull them away from the histone octamer cores.
During this shift of histone-DNA contact points, the DNA presumably becomes accessible to the transcriptional machinery. These complexes serve to maintain chromatin in a repressive configuration by dissociating other chromatin-associated proteins from the DNA, such as the errant TATA-binding protein.
Another class of chromatin-altering factor acts by covalently modifying histone proteins. These modifications include phosphorylation, ubiquitination, ADP-ribosylation, and methylation, but the best-characterized mechanism is acetylation, catalyzed by Histone Acetyl-Transferase enzymes.
The exact consequence of remodeling is dependent on the exact context of nucleosomes at a given promoter and can lead to either (i) activation of transcription or (ii) repression.
In addition to catalyzing nucleosome mobility, chromatin-remodeling factors can enhance the access of DNA-binding factors and nucleases to DNA packaged into chromatin.
These activities are also consistent with the ability of remodeling factors to disrupt histone-DNA interactions in the nucleosome.
ATP-dependent chromatin remodelling
ATP-dependent chromatin remodelling enzymes act to alter chromatin structure during gene regulation.
The functions of ATP-dependent chromatin-remodelling enzymes have been studied in several mammalian differentiation pathways, revealing cell-type-specific and gene-specific roles for these proteins that add another layer of precision to the regulation of differentiation.
ATP-dependent remodelling has a role in regulating the balance between proliferation and differentiation, and have uncovered intriguing links between chromatin remodelling and other cellular processes during differentiation, including recombination, genome organization and the cell cycle.
Studies of the ATPase motors that drive these enzymes support the notion that they function as ATP-dependent DNA translocases with limited processivity. The action of these enzymes on nucleosomes results in the alteration of nucleosome positioning and structure.
ATP-dependent chromatin remodelling can also either remove or exchange histone dimers between nucleosomes. This provides a new means by which the incorporation of histone variants can be directed. Additional observations support roles for ATP-dependent remodelling enzymes throughout the transcription cycle.
chromatin remodeling factors
chromatin remodeling complexes
chromatin modifying complexes (chromatin modifiers)
ATP-dependent chromatin remodelling
Pathology (chromatin remodeling disorders)
Disruption of chromatin remodeling mechanisms gives rise to transcriptional chaos and leukemic transformation such as APL (French-American-British [FAB] M3).
Syndromes of disordered chromatin remodeling are unique in medicine because they arise from a general deregulation of DNA transcription caused by mutations in genes encoding enzymes which mediate changes in chromatin structure.
These mutations result in a loss of proper regulation of chromatin structure, which in turn causes deregulation of gene transcription and inappropriate protein expression.
Some of the genetic diseases that arise as a consequence of disordered chromatin remodeling include: Alpha-Thalassemia/Mental Retardation Syndrome, ATR-X (ATM/Rad3-related); Rett Syndrome (RS); ICF (Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome); RSTS (Rubinstein-Taybi Syndrome), and CLS (Coffin-Lowry Syndrome).
X-linked alpha-thalassemia/mental retardation syndrome (ATR-X)
immunodeficiency-centromeric instability-facial anomalies syndrome (ICF)
rhabdoid tumor syndrome
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