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Identification of genetic networks interacting with COUP-TF II to determinate the atrial cardiac cells identity by the SMyHC III promoter

Grant number: 15/12549-2
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): September 01, 2015
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Biology
Principal Investigator:José Xavier Neto
Grantee:Luana Nunes Santos
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Associated scholarship(s):18/09839-7 - Atrial selectivity from a complex nuclear receptor driven by androgen receptor: a novel gene regulatory network, BE.EP.DD

Abstract

The cardiac development is a complex process with different pathways. In this project we intent to validate protein-protein interactions that were identified by mass spectrometry and that are likely related to the development of the heart inflow tract (sinus venosus and atrium). Previously, our group identified regulatory elements, controlling atrial-specific expression of SMyHC III promoter (Slow Myosin Heavy Chain III), contained within a Complex Nuclear Receptor Responsive Element (ECRRN). The ECRRN is a 33 base pairs (bp), purine-rich (A/G) sequence, containing putative binding sites for nuclear receptor transcription factors. One of the best characterized nuclear receptors is the orphan nuclear receptor COUP-TF II (Chicken Ovalbumin Promoter-Transcription Factor II), playing pivotal roles in many biological processes, such as angiogenesis and atrial development. In cell transactivation assays COUP-TF II has been shown to activate the SMyHC III promoter. Experiments overexpressing COUP-TF II in HEK293T cells, followed by immunoprecipitation and mass spectrometry analysis, suggest that several proteins, immunoprecipitated with COUP-TF II, are known to interact with Glucocorticoid Receptor (GR), Androgen Receptor (AR) and p53. Our preliminary results suggest a new concept to understand the atrial-specific regulation whereby specificity lays mainly through protein-protein interactions between nuclear receptors and, possibly, corregulators. Then, our aim in this project is to elucidate the COUP-TF II interaction with these receptors and nuclear corregulators and identify new factors in the regulatory pathways driving the atrial-specific expression of SMyHC III promoter during the development of the heart inflow tract. (AU)