Hypoxia Reprograms Microrna Targetome in Vascular Endothelial Cells

Presentation Number: LB SUN 33
Date of Presentation: April 2nd, 2017

Feng-Mao Lin*1 and Yifei Miao2
1Beckman Research Institute, City of Hope, 2Beckman Research Institute, City of Hope, Duarte, CA

Abstract

Hypoxia is a common condition imposed on vascular endothelial cells (ECs) in a multiplitude of physiological and pathophysiological conditions. In response to hypoxia, vascular endothelial cells (ECs) selectively upregulate a panel of angiogenic molecules while downregulating anti-angiogenic factors. Such an intricately coordinated network requires both transcriptional and post-transcriptional controls, e.g., those mediated by microRNAs. We previously demonstrated that hypoxia induces a group of hypoxia-responsive miRNAs (HRMs) including Let-7 and miR-103/107, which jointly suppress Argonaute 1 (AGO1), a key components of miRNA-induced silencing complex (miRISC). Inhibiting this HRM-AGO1 pathway resulted in inhibition of hypoxia-induced angiogenesis. To profile the global reprogramming of AGO1-mediated miRNA targeting in hypoxic ECs, we employed individual-nucleotide resolution Cross-Linking and ImmunoPrecipitation Sequencing (iCLIP-seq). In conjunction with mRNA- and miRNA-sequencing, CLIP-seq reveals the HRM-mediated targetome underlying hypoxia-induced endothelial response. Furthermore, our data suggest that HRMs modulate a number of pathways crucial for endothelial response to hypoxia in various disease conditions such as cancer and pulmonary arterial hypertension. Collectively, our study identifies the bona fide targetome of HRMs, which may establish a new paradigm of AGO1-miRNA-regulated gene expression in ECs responding to hypoxic stress.

 

Nothing to Disclose: FML, YM