HIF1A-AS2 Regulates Hypoxia-Driven HIF Isoform Switching in Human Endothelial Cells
- 1Uniwersity of Wroclaw
Abstract
Hypoxia-inducible factors (HIFs) are central regulators of cellular adaptation to low oxygen, with a well-documented transition from HIF-1 to HIF-2 signaling during prolonged hypoxia. Here, we investigate the role of a natural antisense transcript of HIF1A, HIF1A-AS2, in modulating this transition in human endothelial cells (ECs). Genome-wide expression profiling revealed a strong hypoxia-induced upregulation of HIF1A-AS2 that coincided with a marked reduction in HIF1A mRNA levels, whereas EPAS1 remained stable. Interestingly, this negative correlation was consistent across multiple EC types and supported by silencing experiments which demonstrated that both HIF-1 and HIF-2 contribute to HIF1A-AS2 induction. Knockdown of HIF1A-AS2 partially restored HIF1A expression and increased HIF-1 protein and functional activity, as evidenced by elevated VEGFA and GLUT1 expression. Genomic analysis identified HIF-1 and HIF-2 binding motifs upstream of HIF1A-AS2, supporting the dual regulation. Furthermore, cancer tissue analysis revealed frequent downregulation of HIF1A-AS2, correlating with elevated HIF1A and EPAS1 levels. These findings suggest that HIF1A-AS2 acts as a hypoxia-responsive regulator that limits HIF-1 signaling and facilitates the HIF isoform switch, and suggests implications for endothelial adaptation, angiogenic signaling, and vascular remodeling under chronic hypoxia.
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BibTeX
@misc{barton2026hif1aas2,
title = {{HIF1A-AS2 Regulates Hypoxia-Driven HIF Isoform Switching in Human Endothelial Cells}},
author = {A. Barton and A. Wiech-Walow and P. Czechowicz and A. Cabaj and L. Schaefer and J. F. Collawn and R. Bartoszewski},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764826},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764826v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - HIF1A-AS2 Regulates Hypoxia-Driven HIF Isoform Switching in Human Endothelial Cells
AU - A. Barton
AU - A. Wiech-Walow
AU - P. Czechowicz
AU - A. Cabaj
AU - L. Schaefer
AU - J. F. Collawn
AU - R. Bartoszewski
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764826
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764826v1
AB - Hypoxia-inducible factors (HIFs) are central regulators of cellular adaptation to low oxygen, with a well-documented transition from HIF-1 to HIF-2 signaling during prolonged hypoxia. Here, we investigate the role of a natural antisense transcript of HIF1A, HIF1A-AS2, in modulating this transition in human endothelial cells (ECs). Genome-wide expression profiling revealed a strong hypoxia-induced upregulation of HIF1A-AS2 that coincided with a marked reduction in HIF1A mRNA levels, whereas EPAS1 remained stable. Interestingly, this negative correlation was consistent across multiple EC types and supported by silencing experiments which demonstrated that both HIF-1 and HIF-2 contribute to HIF1A-AS2 induction. Knockdown of HIF1A-AS2 partially restored HIF1A expression and increased HIF-1 protein and functional activity, as evidenced by elevated VEGFA and GLUT1 expression. Genomic analysis identified HIF-1 and HIF-2 binding motifs upstream of HIF1A-AS2, supporting the dual regulation. Furthermore, cancer tissue analysis revealed frequent downregulation of HIF1A-AS2, correlating with elevated HIF1A and EPAS1 levels. These findings suggest that HIF1A-AS2 acts as a hypoxia-responsive regulator that limits HIF-1 signaling and facilitates the HIF isoform switch, and suggests implications for endothelial adaptation, angiogenic signaling, and vascular remodeling under chronic hypoxia.
ER -