DMMC Course: EPIGENETICS: FROM MECHANISMS TO MEDICINES

1240-1330 Monday 25 June 2007. O’Reilly Hall, University College Dublin.

The histone code
Prof Bryan M.Turner (University of Birmingham Medical School, UK)

The enzyme-catalyzed acetylation of the N-terminal tail domains of core histones provides a rich potential source of epigenetic information. This may be used both to mediate transient changes in transcription, through modification of promoter-proximal nucleosomes, and for the longer-term maintenance and modulation of patterns of gene expression. The histone modifying and demodifying enzymes (HAT, HDACs, HMTs etc) can be targeted to specific regions of the genome and show varying degrees of substrate specificity, properties that are consistent with a possible role in maintaining a dynamic, histone modification-based epigenetic (histone) code. Histone modifications may operate (ie. exert a functional effect) either through non-histone proteins that bind in a modification-dependent manner, or through direct effects on chromatin structure.
Antibody based techniques, primarily immunofluorescence microscopy and chromatin immunoprecipitation (ChIP) have proved invaluable in analysis of the functional effects of histone modifications and are central to our attempts to demonstrate the existence of an epigenetic (or histone) code. The range of antibodies available and their specificities continue to improve and expand, but even with this improved set of reagents, we still face major experimental and conceptual difficulties. One of the most problematic is the need to distinguish between short-term changes in histone modification associated with ongoing processes, such as transcription and DNA replication and repair, and changes that have longer term effects, namely transmission of patterns of gene expression, or the potential for gene expression, from one cell generation to the next. Changes in histone modifications that accompany short-term processes are crucially important, but their role here is as mediators of protein-protein interactions and intermediates in nuclear signalling pathways. I will argue that an epigenetic code, to be worthy of the name, must comprise modifications that are essentially long-term and heritable. Technical and conceptual problems arise because modifications involved in both long-term and short-term effects may be found in the same chromatin regions, and even on the same nucleosome. I will discuss recent work from my own laboratory that addresses these issues.