Regulation of eukaryotic gene expression at the level of chromatin domains

Aim of the proposal is to understand mechanisms of histone modifications (the ‘histone code’ hypothesis) that regulate eukaryotic gene expression at the level of chromatin domains. I will set up a novel system in mammalian cells to systematically analyze causal relationships between induction of histone modifications in a defined chromatin domain and (i) changes in chromatin condensation, (ii) spreading of the induced modification in cis, and (iii) gene activity. Packing of the eukaryotic genome into higher order chromatin structures is tightly related to gene expression. The genome is partitioned into distinct functional domains flanked by boundary elements that help to assure independent regulation of the function of such domains. The mechanism that establishes and maintains functional chromatin domains in relation to gene expression is poorly understood. Posttranslational modifications of histones (i.e. acetylation, methylation, phosphorylation and ubiquitination) have been directly linked with transcriptional regulation and changes in chromatin structure over large distances. These modifications are thought to alter interactions of histones with DNA and with chromatin-associated proteins. The ‘histone code’ hypothesis states that specific patterns of histone modifications facilitate recruitment of non-histone proteins to chromatin, inducing formation of a higher order chromatin structure to either permit or exclude transcription. Histone modifications act in a combinational manner and are also known to affect additional epigenetic signals such as DNA methylation. The precise function(s) of these complex interactions have remained elusive. My aim is to unravel mechanisms of histone modifications that regulate eukaryotic gene expression at the level of chromatin domains. The present research proposal is one of the key foci in cell biology. Particularly, since chromatin structure and function correlate with distinct cell fates during development and may help to discriminate between the developmental potential of stem cells and fully-differentiated cells.