Lead


Lay summary

Background:

Developmental decisions, defining lineage-specific expression patterns, need to be preserved during cell division. This process, termed “cellular or transcriptional memory”, is controlled at the level of chromatin. Two groups of chromatin proteins are responsible for maintaining the differential gene expression patterns characterizing the individual cell types. The Polycomb group (PcG) proteins are required for a stable and heritable silencing of target genes. Conversely, the proteins of the Trithorax group (TrxG) counteract PcG repression and maintain the active expression state. Signals restricted in space and time initiate developmental choices, which are then subsequently maintained by the PcG/TrxG controlled chromatin functions. Hence, the interplay between these chromatin regulators utilizes epigenetic features and forms the molecular basis for the heritability of cell identities. PcG/TrxG chromatin control has been evolutionary highly conserved, ranging from flower development in plants to X chromosome inactivation in mammals. A major site of action for these epigenetic regulators is at promoters of target genes, in particular at promoters with a paused polymerase. PcG protein complexes place and bind histone modifications at repressed target genes, resulting in a reduced accessibility of the nucleosomal structure and in an inhibition of the transcriptional elongation process. The counteracting TrxG proteins exhibit functions, which open nucleosomal structures and allow the transcriptional machinery to enter processivity. Interestingly, we observed that Hsp90, a molecular chaperone and important sensor of environmental stress signals, cooperate with the PcG/TrxG system at paused polymerases.

 

Goals:

Our understanding of transcriptional memory stems primarily from the involvement of the PcG and TrxG in maintaining developmental decisions. In this project we would like to expand the view by analyzing whether environmentally induced stress conditions can impose epigenetically heritable gene expression states. We will used cellular systems inducible by environmental stimuli and combine new methodologies, like GRO-seq and PAR-CLIP, to study the dynamic behavior of PcG and TrxG proteins at target promoters and identify the crosstalk between the two groups at the transition from silenced to activated state. This will include the identification and functional analysis of non-coding RNAs found as important companions of PcG-induced repression. We will develop transgenic reporter systems in Drosophila sensing environmental cues and measure whether stress conditions can be imprinted into chromatin and epigenetically inherited through mitosis and eventually even meiosis.

 

Relevance:

Several epidemiological reports have suggested that environmental exposures early in development play a critical role in susceptibility to late-onset diseases such as diabetes and cancer. Some of these conditions may even be inherited to future generations. Hence, an important question is whether environmental stimuli can induce chromatin states, which are heritable in a similar fashion as developmental signal induce the maintenance of cellular identities. Given that several Hsp90 inhibitors are in clinical trials as anti-cancer drugs, it will also be important to further assess the molecular crosstalk this chaperone exerts with the PcG/TrxG system in controlling developmental and stress-induced genes.