| Tumor angiogenesis |
Hypoxia and Angiogenesis Group
Keywords: Hypoxia, Angiogenesis, Genomics, Bioinformatics.
The elucidation of the cellular and molecular responses to hypoxia constitutes an important research topic due to the relevance of this process in cellular physiology and high-incidence pathologies such as cancer and cardiovascular diseases. The Hypoxia Inducible Transcription Factor (HIF) plays a pivotal role in this response by controlling the expression of most of the genes involved in adaptation to hypoxia. The aim of our group is to contribute to the understanding of the transcriptional response to hypoxia and the cellular and molecular mechanisms underlying central adaptation responses like angiogenesis. Our long term goal is to exploit this knowledge to improve clinical management of pathologies in which development of tissue hypoxia is a common feature.
Characterization of the transcriptional response to hypoxia
Ablation of HIF prevents both gene upregulation and repression triggered by hypoxia. However, genome-wide profiling of HIF-binding sites indicates that only gene induction is directly regulated by HIF. To identify the mechanisms responsible for gene repression during hypoxia, we developed a computational approach that, exploiting the vast amount of publicly available ChIP-seq datasets, identified enriched transcriptional regulators. This approach revealed that several subunits of the SIN3A corepressor complex had a significant association to hypoxia-repressed genes. (Tiana et al., Nucleic Acids Res. 2018).
Identification of polymorphisms affecting HIF binding sites and their contribution to disease inter-individual variability
The vast majority of human genetic variation lies in non-coding regions of the genome, but its functional impact in phenotype and disease is almost unknown. We have described that several common SNPs affect the transcriptional response to hypoxia (Ortiz-Barahona et al., Nucleic Acids Res. 2010 and Roche et al., Nucleic Acids Res. 2016). However, a global analysis of comon genetic variability on the response to hypoxia is still lacking. Aiming to fill this gap, we designed an unbiased approach to identify SNPs having a functional impact on HIF binding to chromatin. Using this strategy we have identified over 300 variants conferring allele-specific binding, most of them outside HREs.
Understanding the role of HIFs in endothelial cells during angiogenesis induced by hypoxia
Angiogenesis is the main mechanism of vascular remodeling and a fundamental adaptive response to hypoxia in physiology and disease. Cancer relies on chronic activation of angiogenesis to support unlimited growth and dissemination; therefore halting this process could allow for new therapeutic developments for cancer patients. The role of Hypoxia Inducible Factors (HIFs) in the control of angiogenesis is still incomplete. Our group has revealed that hypoxia imposes an anti-proliferative gene expression signature in endothelial cells. Using angiogenesis models based on the differentiation of embryoid bodies generated from murine stem cells and loss/gain of function genetic approaches for HIFs we are currently elucidating the molecular mechanism involved and its role in the induction of angiogenesis by hypoxia. Our long term goal is to exploit this knowledge to identify molecular targets for the inhibition of hypoxia driven angiogenesis in cancer.