Tumorigenesis by Meis1 overexpression is accompanied by a change of DNA target-sequence specificity which allows binding to the AP-1 element
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Leila Dardaei1,4, Dmitry Penkov1,2, Lisa Mathiasen1, Pranami Bora3, Marco J. Morelli3, Francesco Blasi1
1IFOM, FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milano, Italy
2Department of Experimental Cardiology, Russian Cardiology Research and Production Complex, Moscow, Russia
3Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy
4Present Address: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA
Francesco Blasi, e-mail: [email protected]
Keywords: Meis1, Prep1, AP-1, tumorigenesis, ChIP-seq
Received: April 03, 2015 Accepted: July 23, 2015 Published: August 03, 2015
Meis1 overexpression induces tumorigenicity but its activity is inhibited by Prep1 tumor suppressor. Why does overexpression of Meis1 cause cancer and how does Prep1 inhibit? Tumor profiling and ChIP-sequencing data in a genetically-defined set of cell lines show that: 1) The number of Meis1 and Prep1 DNA binding sites increases linearly with their concentration resulting in a strong increase of “extra” target genes. 2) At high concentration, Meis1 DNA target specificity changes such that the most enriched consensus becomes that of the AP-1 regulatory element, whereas the specific OCTA consensus is not enriched because diluted within the many extra binding sites. 3) Prep1 inhibits Meis1 tumorigenesis preventing the binding to many of the “extra” genes containing AP-1 sites. 4) The overexpression of Prep1, but not of Meis1, changes the functional genomic distribution of the binding sites, increasing seven fold the number of its “enhancer” and decreasing its “promoter” targets. 5) A specific Meis1 “oncogenic” and Prep1 “tumor suppressing” signature has been identified selecting from the pool of genes bound by each protein those whose expression was modified uniquely by the “tumor-inducing” Meis1 or tumor-inhibiting Prep1 overexpression. In both signatures, the enriched gene categories are the same and are involved in signal transduction. However, Meis1 targets stimulatory genes while Prep1 targets genes that inhibit the tumorigenic signaling pathways.
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