P572Pitx2 differently controls the expression of gene embedded microRNAs in cardiac and skeletal muscle cells.

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The Pitx2 gene is a member of the Bicoid-like homeobox family that plays an important role in embryonic left-right signalling and subsequently during cardiac and skeletal muscle organogenesis. Pitx2 misregulation has been as well associated with skeletal and cardiac muscle diseases. Although three Pitx2 isoforms are expressed in mice, Pitx2a, Pitx2b and Pitx2c, only Pitx2c plays a determinant role in left-right signalling and organogenesis. Over the last years we have gained insights into the transcriptional regulatory mechanisms driven by Pitx2 in both cardiac and skeletal muscle. Interestingly, besides playing a role in regulating a large number of protein-coding genes, microRNAs are also regulated by Pitx2. Whereas the functional role of distinct microRNAs in cardiac and skeletal muscle development and homeostasis is progressively emerging, their transcriptional control and the genetic networks in which they are involved remains largely unexplored. Among 34 differentially regulated microRNAs by Pitx2 in either skeletal or cardiac muscle cells, 10 (~30%) display putative Pitx2 binding sites in the -3000 bp proximal promoter sequence, among with other muscle-enriched transcription factor binding sites. Curiously, only two of these microRNAs were intergenic, supporting thus their own transcriptional regulatory mechanisms, while the majority of them were embedded into distinct host genes. Since transcriptional regulation of gene-embedded microRNAs seemed to be modulated in accordance with transcriptional regulation of the host gene, we evaluated the host gene/microRNA expression levels in Pitx2 gain-of-function experiments using Sol8 skeletal muscle and HL-1 atrial cardiomyocytes, respectively. Surprisingly, our data demonstrate that most of these microRNAs are independently regulated from its host gene, and moreover such transcriptional regulation is cell-type specific. We are now working to establish the mechanisms by with Pitx2 can exert this microRNAs transcriptional regulation.

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