IN SILICO SEARCH FOR CIS REGULATORY ELEMENTS (CRMS) IN THE TRANSCRIPTIONAL REGULATION NETWORK OF STEMNESS: PROTEIN ACTION OF TGFBETA / SMAD PATHWAY.

CAROLINA PEREZ CASTRO

Conferencia; 16th TWAS-ROLAC Young Scientists Conference; 2014

Brazilian Academy of Science

Stem cells (SCs) can be propagated in vitro under conditions that promote self-renewal. The transcription factors Oct-4, Sox2 and Nanog constitute a core to maintain self-renewal properties in pluripotent SCs. The activities of the TGFbeta family members are other essential regulators of SCs properties and cell fate decision, although, the underlying molecular mechanisms are not known in details. Many critical signaling pathways necessary for SCs identity are also activated in tumor cells, particularly in cancer initiation cells (CIC) or CSC. CIC share many characteristics of SCs, including self-renewal and potentiality for cell differentiation, which are considered to be main drive for the metastasic and recurrence behavior of cancer. The main goal of our research activities is to characterize gene expression regulation in stem cells (SCs) and cancer stem cells (CSC) by TGFbeta signaling, to elucidate the molecular mechanisms conferring SCs properties. The regulation of transcription occurs through the coordinated action of multiple transcription factors (TFs) that bind cooperatively to cis regulatory elements (CRMs) of target genes. These CRMs generally contain certain number of TFs binding sites (TFBSs). Even experiments performed by chromatin immunoprecipitation followed and sequencing (ChIP-seq) have been very effective in detecting TFBSs and location of CRMs at the genomic level; they are very expensive and often difficult to be reproduced experimentally. Therefore, as an alternative, we designed a novel bioinformatics algorithm (INSECT) that assists for the identification of transcription factor binding sites (TFBSs) and cis-regulatory modules (CRMs) for gene(s) of interest. In particular, we studied genes (candidate genes) that might be under the co-regulation of the core transcriptional factors and the TGFbeta/SMAD pathway. Identifying those novel regulators of SCs properties may provide important insights for developmental biology and regenerative medicine and contribute to a better understanding of the biology of CSCs and cancer development.