Chromatin can act as a barrier impeding the access of regulatory proteins to the genome both in vivo (Grunstein, 1997) and in vitro (reviewed by Owen-Hughes and Workman, 1994). This means that any process requiring access to the genetic information must first contend with chromatin, and would suggest that unfolding of chromatin might represent an important step in gene regulation.

Amongst the first evidence to support this concept was the findings that changes in the susceptibility of chromatin to nuclease digestion correlated with changes in gene expression (reviewd by Gross and Garrard, 1988). Now a number of distinguishing properties of active chromatin have been further characterisezed including:

• DNaseI sensitivity

  reviewed by Gross and Garrard, 1988

• Acetylation of histones

  Allfrey et al, 1964; Hebbes et al, 1994; Jeppesen and Turner, 1993; Kuo et al, 1998; Kadosh and Struhl, 1998

• Methylation of DNA

  Tazi and Bird, 1990

• Histone H1 content

  Kamakaka and Thomas, 1990

Until recently, the factors responsible for these changes in chromatin structure were not known. However, over the last five years a number of multiprotein complexes have been characterised that appear to function to unfold chromatin during gene regulation. These include chromatin remodelling complexes that unfold chromatin in an ATP-dependent fashion, histone acetyltransferases (HATs) and histone deacetylases. A number of the components of these complexes are found to be directly associated with components of the basal transcription apparatus making it clear that the creation of appropriate chromatin structure is an integral step in the process of gene regulation (Kadonaga, 1998).

The recent solution of the crystal structure of the nucleosome at 2.8 A resolution (Luger et al, 1997) provides a framework upon which the mechanisms by which acetylation alters chromatin structure can be built. In addition, the technology used to purify recombinant histone proteins provides a means by which new methods can be generated to probe chromatin structure (see for example site directed hydroxy radical mapping; Flaus et al, 1996; Flaus and Richmond, 1998).

Despite the undeniably important role chromatin remodelling plays in gene regulation, little is known about exactly how it exerts this effect. We are interested in determining how these activities function.

Our main areas of interest are:

1. Mechanisms of ATP-dependent chromatin remodelling
2. Effects of acetylation on chromatin structure
3. How does RNA polymerase transcribe through chromatin
4. Chromatin and human disease

5. References (launches in separate window)