PgmNr M5066: SOX9 in developing heart valves and adult valve disease.

Authors:
P. A. Hoodless 1,3 ; V. C. Garside 1 ; M. Bilenky 2 ; R. Cullum 1


Institutes
1) Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, CA; 2) Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, CA; 3) Dept. of Medical Genetics, University of British Columbia, Vancouver, BC.


Abstract:

Abnormal heart valve formation leads to a third of all cardiovascular birth defects. Valve defects can have detrimental effects on heart function and can lead to an increase in disease susceptibility. SOX9 is an essential transcription factor required in the development of the embryonic heart valves in mouse. Without its expression in this tissue, embryos have functional heart defects, fail to thrive, and die around E13.5. Previously, we identified the global transcriptional targets of SOX9 in embryonic day (E) 12.5 developing atrioventricular canal (AVC). Unlike many other transcription factors, SOX9 binding is heavily biased to the transcription start site and adjacent promoter regions. we have found that SOX9 has a universal role in regulation of cell cycle and proliferation genes across multiple cell types. Furthermore, analysis of heart ChIP-Seq libraries and transcriptome profiles on Sox9-deficient E12.5 heart valves revealed that SOX9 directly controls a critical network of transcription factors known to be involved in heart valve development. We have now generated SOX9 ChIP-seq data from E10.5 embryonic hearts, a time at which SOX9 expression is initiating in the AVC. In addition, we have used histone modification ChIP-Seq data to evaluate the chromatin landscape around the SOX9 binding sites. These histone modifications exhibit asymmetric patterns around the SOX9 site. Integration of data from the earlier time point (E10.5) builds a more complete picture of the regulation by SOX9. Additionally, from motif analysis of this data as well as proteomic analysis, critical factors bound with or to SOX9 in the developing valve have been identified. Our examination of the underlying mechanisms of SOX9 binding, gene expression changes when SOX9 is absent provides insights into the functional role that SOX9 plays in heart development.