Jason Carroll scientific summary

Nuclear receptor transcription laboratory

Previous and current research

My interests lie in understanding the molecular mechanisms of Estrogen Receptor (ER) transcription and how this influences cancer progression and response to hormone therapies. A combination of Chromatin Immunoprecipitation (ChIP), that permits in vivo protein-DNA analysis, with tiling microarrays that cover all 1.5 billion bp of non-repetitive sequence, allowed us to map genome-wide ER and RNA PolII binding sites. These analyses have identified the discrete regions hidden within the genome that function as putative cis-regulatory elements in ER-mediated transcription. The sequence information within these binding sites permits the identification of co-operating factors that can both augment and inhibit ER transcription. This use of binding site location information and sequence information is allowing us to piece together the complex issue of distal enhancer-promoter communication. It also provides insight into the specific regions within the chromatin that are likely to be sites of perturbations that may lead to changes in hormone responsiveness.

Future projects

We aim to extend on our recent characterisation of ER binding sites and gene transcription events within breast cancer cell models, by defining underlying mechanisms of protein-chromatin interactions in various hormonal conditions. These include characterising the estrogen-induced communication between proteins at distal enhancers that initiate transcription and the proteins at the promoters that execute it. We also aim to develop in vivo methods for analysing protein recruitment to known sequences in a chromatin context, in order to assess the in vivo sequence requirements for protein loading at enhancers and promoters of interest. We are currently mapping genome-wide ER binding sites in the presence of tamoxifen and aim to identify the factors required for transcriptional inhibition. This complete body of data will subsequently be used to screen tumour samples in an attempt to identify common sequence changes that may contribute to differences in hormonal status.