Molecular mechanisms of histone modification function.

The many functions that a eukaryotic cell carries out require that its geneticmaterial ismaintained, read and translated in a highly organized manner. Besides rapid reaction to external stimuli long-term differentiation and developmental programs need to be faithfully executed. The blueprint for these processes resideswithinDNA as inheritablematerial. However, the many differences in the biology of diverse organisms and individual cells cannot be explained solely on the basis of different gene sequences and content. Epigenetic processes direct organized and specific use of a given genome in a time and space resolved manner. The molecular target of epigenetic signaling is chromatin, the packaging form of the genetic material in eukaryotic cells. Here, DNA is complexed with histone proteins (linker histones of H1-type and core histones H2A, H2B, H3 and H4) in repeating units called nucleosomes. While the molecular architecture of all nucleosomes is essentially the same throughout the genome, chemical modifications of DNA (e.g. by methylation) and in particular of the different histone proteins mark locally and globally distinct areas of chromatin. Since the initial description of general histone acetylation as well as other modifications by Vincent Allfrey in the 1960s a waste number of different types and sites of posttranslational modifications on the core and linker histones have been recognized. Combining data from different experimental model systems and using varying technical approaches more than 150 marks on the histone proteins have been mapped until now. In agreement with a role in directing the functional state of associated DNA these modifications appear to function in all kinds of biological processes that eukaryotic genomes undergo such as for example transcription, replication, recombination and repair. Not surprisingly, varying patterns of histone modifications are implicated in normal as well as disease developmental processes. Immediate regulatory roles of histone modifications in cellular signaling aswell as their causal function in directingusage of the genetic material were questioned for a long time. The major breakthrough in this field came by the identification and characterization of enzymes and enzyme systems controlling histone modification state almost two decades ago. The findings that previously studied transcriptional regulators act in modifying and demodifying histones spurred huge interest into histone marks promising molecular insights into complex epigenetic phenomena. Much progress has been made during the last 20 years not only to link individual and combinations of histone modifications to defined biological states of genomes but also in our understanding of the ways these marks work on a biochemical level. These days, large-scale efforts are not only devoted to globally map discrete patterns of histone modifications in different cellular states but also to deduce the complex logic governing this intricate