Identification of genes regulated by the several HIF-3a isoforms: development of tumor patients transcriptomics data analysis tool

• Grant number: 15/26059-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2016
• End date: February 28, 2018
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Fábio Malta de Sá Patroni
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Because of its importance in metabolic adaptation and progression of cancer, obtain functional information about the HIFs that may answer their mechanisms of action is of paramount importance for the understanding of the disease. Of particular interest is the least studied isoform, HIF-3±, and its different variants by alternative splicing. Three variants (-3±1, -3±1 and -±9) have bHLH domain interaction to DNA and NTAD regulation domain of gene transcription in a way that potentially directly regulate gene transcription of target genes. Indeed, HIF-3±9 has been shown regular one set of genes themselves. Other 3 (-3±4, -3±5 and 3±7) have neither the bHLH domain nor NTAD domain and can promote regulation not as active elements, but as suppressors, as already proven to HIF-3±4. The current group in which this proposal fits has recently been published a paper which described crystallographic structure of PASb domain (common to all the HIF-3±1, 3, 5, 7 and 9 variants) containing a fatty acid in an extended hydrophobic cavity. Subsequent studies have characterized this molecule and showed that the interaction is important for the domain stability and interaction with HIF-1². The findings have been extended to bioinformatics studies using data from tumors of available patients in public bank, which show that the transcript of HIF-3±9 isoform is more present in genitourinary tumors and nerve tissue and that increased expression of it was associated with genetic changes linked to matrix remodeling and potentially metastasis. This preliminary study brought us precious hints about the potential involvement of HIF-3±9 isoform with the metastatic process of a group of tumors. Knowing the set of genes potentially regulated by it, and other variants in tumor tissues will help to understand the overall function of the isoform as well as the details imposed by the existence of variations and its specific association with different tumor types and process. For this, we are going to use transcriptomics data from tumors of patients available in public banks and R platform bioinformatics tools available, plug them into a single package that will automate the analysis, and, with this package, define genes differentially expressed by variants. With possession of this data, we will check for the HIFs responsive elements in the promoter regions in order to validate them as potentially regulated by this transcription factor, and define enriched cellular pathways by each of the variants.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DOS REIS, LARISSA MENEZES; ADAMOSKI, DOUGLAS; OLIVEIRA SOUZA, RODOLPHO ORNITZ; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; CORREA-DA-SILVA, FELIPE; DE SA PATRONI, FABIO MALTA; DIAS, MARILIA MEIRA; CONSONNI, SILVIO ROBERTO; MENDES DE MORAES-VIEIRA, PEDRO MANOEL; et al. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. Journal of Biological Chemistry, v. 294, n. 24, p. 9342-9357, JUN 14 2019. (15/15626-8, 14/17820-3, 15/25832-4, 14/18061-9, 15/26059-7, 16/06034-2, 17/06225-5, 13/23510-4, 14/06512-6, 14/15968-3)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

PATRONI, Fábio Malta de Sá. Identification of genes regulated by the different HIF-3alpha isoforms: tool development for tumor data analysis. 2019. Master's Dissertation - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.