Serum response factor (SRF) is a transcription factor of the MADS box family that regulates essential structural and metabolic genes in many tissues. Using a mouse Cre-Lox model, we have shown previously that SRF inactivation can result in severe cardiac and intestinal failure as well as angiogenic defects.
We have performed transcriptomic analyses of gene expression alteration in the cardiac and vascular system following SRF inactivation (see other abstracts) and we found a large number of down-regulated genes but an even larger number that are up-regulated after SRF inactivation. This latter result was partly unexpected since SRF is mainly known as a positive regulator of transcription. While various hypotheses can account for this up-regulation, we chose to focus on the potential role of SRF in the control of miRNAs, which are endogenous small RNAs that can inhibit the expression of other mRNAs. Indeed, recent bioinformatic analyses revealed that more than 40 microRNAs contain SRF target sequences in their promoter region, suggesting a possible broad regulatory role of SRF for these microRNAs. It has already been shown by others that SRF regulates miR-1 and miR-133 expression during heart development, those miRs being essential for correct cardiogenesis and the control of cardiac hypertrophy. The aims of this project are: 1) To analyse the role of SRF in the regulation of microRNAs in the adult heart and vessels of mice by a transcriptomic approach and ChIP on Chip approach ; 2) To study the biological role of microRNAs regulated by SRF and their implications in development of cardiovascular disease.
To analyse the role of SRF in microRNA regulation, we have started to extract total RNA from hearts of SRF conditional knockout mice at different stages and in basal and hypertrophic settings. Preliminary analysis of global microRNA expression profile of these samples using Illumina V2 microRNA beadarrays and characterization of the expression of putative SRF MiR targets by quantitative RT PCR will be presented.Le texte complet de cet article est disponible en PDF.