Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation in early hypoxia.

Fransky Hantelys,Leila H Diallo,Edith Renaud-Gabardos,Eric Lacazette,Anthony K Henras,Angelo Parini,Florian David,Anne-Claire Godet,Laetitia Ligat,Françoise Pujol,Yasufumi Sato,Florence Tatin,Barbara Garmy-Susini,Isabelle Ader,Anne-Catherine Prats

doi:10.7554/elife.50094

Abstract

Hypoxia, a major inducer of angiogenesis, triggers major changes in gene expression at the transcriptional level. Furthermore, under hypoxia, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here, we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) that is able to bind RNA and to activate the FGF1 IRES in hypoxia, but which tends to inhibit several IRESs in normoxia. VASH1 depletion has a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process triggering new vessel formation in ischemic heart.

Highlights

Hypoxia constitutes a major stress in different pathologies including both cancer and ischemic pathologies where artery occlusion leads to hypoxic conditions
HL-1 cells were submitted to increasing durations of hypoxia, from 5 min to 24 hr, and their transcriptome was analyzed on a Fluidigm Deltagene PCR array targeting 96 genes of angiogenesis, lymphangiogenesis and/or stress (Figure 1, Figure 1—figure supplement 1, Supplementary file 1)
We show that translational control, revealed by mRNA recruitment into polysomes during hypoxia, regulates the majority of the genes involved in angiogenesis and lymphangiogenesis

Summary

Introduction

Hypoxia constitutes a major stress in different pathologies including both cancer and ischemic pathologies where artery occlusion leads to hypoxic conditions. IRESs are present in the mRNAs of several (lymph)angiogenic growth factors in the FGF and VEGF families, suggesting that the IRES-dependent mechanism might be a major way to activate angiogenesis and lymphangiogenesis during stress (Morfoisse et al, 2014; Godet et al, 2019; Morfoisse et al, 2016; Huez et al, 1998; Martineau et al, 2004; Stein et al, 1998; Vagner et al, 1995). Most studies of the role of hypoxia in the regulation of gene expression have been performed in tumoral hypoxia, it has been reported that tumoral angiogenesis leads to the formation of abnormal vessels that are non-functional, differing strongly from nontumoral angiogenesis that induces formation of functional vessels (Jain, 2005). VASH1 depletion has a wide impact on the recruitment of (lymph)angiogenic factor mRNAs into polysomes, suggesting that this protein can regulate translation positively or negatively in early hypoxia

Results

Discussion

C VASH1 predicted RNA binding domains

D VASH1 protein subcellular localization F

Materials and methods