Thursday, July 24, 2008

Revealing the Chromatin Structure of Human Promoters

Source: Ozsolak et al. (2007). High-throughput mapping of the chromatin structure of human promoters. Nat Biotech 25(2):244-248.

There are many models surrounding the effects of chromatin remodeling and how it affects the genetic context in which the genes are transcribed and expressed. However, without a precise map of where the nucleosomes are, we cannot tell whether they are remodeled or not given a certain stimulus. This paper represents a series of similar studies using tiling arrays (or more recently high-throughput sequencing) to find the nucleosome positionings. Subjecting nucleosome-bound DNA to micrococcal nuclease (MNase) will result in the degradation of the linker fragments while the bound segments will be protected by the histones. In theory, finding the sequence of the fragments surviving MNase should give us the nucleosome positions in the genome. Tiling arrays are suitable for this purpose, helping us to find the parts of the genome that remains intact after digestion.

In practice, the data is way noisier than we might assume due to many reasons (e.g. DNA bound to proteins other than nucleosomes or simply shortcomings in the technical methods). The significance of this paper is in developing computational methods for cancelling out the noise and improving the signal to noise ratio. They effectively succeed in recapitulating the nucleosome positionings that are already known in case of certain promoters (e.g. see the figure below).


Upon mapping the nucleosome positions, the authors proceed to make useful observations. For example, they show that in the highly expressed genes, the promoter region is stripped off the nucleosomes. They also make the case that certain binding elements fall outside of nucleosome-bound region, meaning they are probably bound by active transcription factors.

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