Mechanisms of tissue-specific gene transcription

One of the most fundamental processes in all living organisms is expression of the genetic information.

We will investigate how transcriptional enhancers communicate with promoters to generate tissue-specific patterns of gene expression.

Our preliminary data refute the textbook view of enhancer-promoter looping for 190 patterning genes in the Drosophila embryo. An alternative model for enhancer-promoter communication that does not involve direct physical contact will be tested.

In this model, the acetyltransferase p300/CBP becomes activated at the enhancer and generates a gradient of acetylated proteins that reach the promoter to trigger transcription.

This model will be tested in vivo with cutting-edge genomic, genetic and genome engineering technologies already established in the lab (e.g. PRO-seq, CUT&Tag and Cas9-engineering).

We will investigate the role of the CBP acetylase and the P-TEFb kinase in tissue-specific transcription and enhancer-promoter communication by i) optogenetic inactivation of CBP ii) generating a catalytically inactive CBP allele iii) mapping genomic regions bound by activated CBP iv) identifying targets of CBP acetylation focusing on P-TEFb v) testing the activity gradient model by bioinformatic analyses, targeting different doses of dCas9-CBP to enhancers, and by live imaging of reporter genes.

Our results may provide a completely new and far-reaching answer to the longstanding question of how enhancers communicate with promoters.