Question

How do eukaryotes use chromatin remodeling to regulate transcription? Why have some cancers been shown to be associated with mutations in genes involved in chromatin remodeling?

Answer 1

In eukaryotes, the transcription can be blocked when the TATA box( promoter sequece for transcription beginning in eukaryotes) and flanking sequences are wound up in nucleosomes, which makes them unable for the access of RNA polymerase 11 complex. Activation of transcription would require the blocking nucleosome to be removed or moved elsewhere. These changes in nucleosome position is called chromatin remodelling. Chromatin remodelling takes place mainly in 3 ways. One is by changing the relative position of few nucleosomes or by changing the spacing of the nucleosomes over a long distance. this is brought about by ATP dependent chromatin remodelling complex. Second way of chromatin remodelling is by the removal of histone octomers. This is called histone eviction. This is also done with help of ATP dependent chromatin remodelling complexes. The third way is by the replacement of histones with a varient histone. In all these models the tail of the histones are subjected to either methylation, acetylation or phosphorylation. Chromatin remodelling can also be done by the modification of the core histones by the proteins such as hitone acetyltransferaces, deacetylases, methyl transferases and kinases.

The result of chromatin remodelling is either the 'open' or 'close' state of nucleosome, by which the transcription regulation occurs. The 'open' state of nucleosomes are brought about by the action of histone acetyl transferases, ATP dependent chromatin remodelling complexes and transcription factors. they make the gene open for transcription.  The 'closed' state of nucleosome is brought about by the action of acetylation and methylation of histones by the action of histone deacetylases and histone methyl transferaces. They bring about the tight packaging of the DNA around histones making the gene unavailable for transcription.

The genes encoding proteins for chromatin remodelling is subjected to recurrent mutations especially to the ATP dependent chromatin remodelling complexes. these mutations can affect the DNA methylation, histone modification and even in the nucleosome composition. All these mutations result in either the suppression to transcription of genes ar to the expression of some unwanted genes resulting in tunourogenesis or cancer. The understanding of these factors and enzymes and their role in cancer offers potential for the developmnt of new cancer theraupetics.