New view of chromatin and gene activity

A genome - the DNA instructions for an organism - does not act alone. DNA is packaged with proteins into 'chromatin', which may be more or less tightly condensed. A popular proposal is that active genes are in 'open' chromatin (to allow access to them) and inactive genes are in tightly packed 'compact' chromatin.

In landmark research published in Cell, a team from the Wellcome Trust Sanger Institute and the MRC Human Genetics Unit in Edinburgh show that this simple view is wrong.

For the first time, the entire genome was analysed using high-throughput science methods - genome arrays - an approach that was not possible only four years ago. The results show that regions that are rich in genes tend to be in open chromatin structures, whereas regions poor in genes tend to be in compact chromatin. However, open chromatin can contain inactive genes and compact chromatin can contain active genes.

Dr Nigel Carter, Head of Molecular Cytogenetics at the Wellcome Trust Sanger Institute, said: "It is only with the finished Human Genome Project that we can look across the global landscape of the human genome. Allied to developing high-throughput research tools, entirely new experiments are becoming possible that will illuminate the darker regions of genome biology."

"Our results show for the first time that it is not simply gene activity that determines chromatin structure (or is determined by chromatin structure). The existing concept - that open chromatin is an absolute requirement for gene activity - is not supported by this study."

Regions of open chromatin extended over several genes and were delimited by sharp boundaries. The team suggest that open chromatin represents regions that are poised for gene activity, perhaps as a precursor to remodelling chromatin to allow transcription.

"We set out to examine whether chromatin in some parts of the human genome is more or less tightly packaged than in other regions" says Head of the Edinburgh team, Wendy Bickmore at the MRC Human Genetics Unit. "An analogy for the genome is a book with thousands of pages. Most of the pages will be closed shut but, because of changes in chromatin structure, some pages will be open."

The authors' new research indicates that genes that are active in a wide range of cells (housekeeping genes) tend to be clustered in regions of open chromatin, so that they can easily be read when required. Furthermore, they suggest that there has been a selective pressure during evolution to maintain the integrity of these regions.

Open chromatin also appears to be the preferred route for 'infection' of our genome by transposable DNA elements and viruses: sites of integration of HIV correspond well with open chromatin. Understanding how the open and closed chromatin structures are formed, and how genes in closed chromatin can be read, is going to be especially important for understanding how different genes are expressed in different cells. Further studies will show whether open and closed chromatin structures are changed in disease such as cancer.

http://www.sanger.ac.uk

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