A231: Signalling to the epigenome: how TGF-b superfamily ligands regulate gene expression via chromatin

Davide Martino Coda1,Tessa Gaarenstroom1,Harshil Patel2,Phil East2,Aengus Stewart2,Caroline Hill1

1The Francis Crick Institute, Laboratory of Developmental Signalling, London, UK,2The Francis Crick Institute, Bioinformatics and Biostatistics Group, London, UK

Presenting date: Monday 2 November
Presenting time: 12.20-13.10

Background

TGF-b superfamily ligands elicit their biological effects by inducing new programmes of gene expression. Although the Smads, which are the effectors of the downstream signalling pathways, are well established as transcriptional regulators, how exactly they function is not well understood. They regulate transcription by remodelling the chromatin template, but the precise sequence of events that occur at the target genes remains obscure.

Method

I am attempting to unravel the interaction between the Smads and the epigenome by understanding on a genome-wide scale how the chromatin landscape changes in response to different modes of signalling. To achieve this goal we use the embryonic teratoma cell line P19, combining a broad range of cutting edge techniques, including ChIP-seq and RNA-seq. I am characterising the kinetics of changes in different histone modifications in response to signal, and defining the cause–effect relationship with the observed transcriptional responses.

Results

Initial results indicate rapid changes in specific histone marks (H3K27ac-H3K9ac) and nucleosome remodelling occuring at the enhancers and promoters of Smad2 target genes upon signalling activation, along with Pol II phosphorylated at both Ser5 and Ser2 inducibly detected on the gene body of induced genes.

Conclusion

We are integrating analysis of these data with target gene expression kinetics and Smad2 genome occupancy to elucidate Smad-mediated transcriptional response, clarifying the sequence of events in terms of changing in chromatin landscape and activity of RNA polymerase II in response to signalling.