FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

Yuri Miyamura; Shunsuke Kamei; Misaki Matsuo; Masaya Yamazaki; Shingo Usuki; Keiichiro Yasunaga; Akiyoshi Uemura; Yorifumi Satou; Hiroto Ohguchi; Takashi Minami

doi:10.1016/j.isci.2024.109161

FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

iScience. 2024 Feb 16;27(3):109161. doi: 10.1016/j.isci.2024.109161. eCollection 2024 Mar 15.

Authors

Affiliations

¹ Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan.
² Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-8556, Japan.
³ Division of Medical Biochemistry, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan.
⁴ Liaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto 860-8556, Japan.
⁵ Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁶ Division of Disease Epigenetics, IRDA, Kumamoto University, Kumamoto 860-0811, Japan.

Abstract

Forkhead box O (FOXO) family proteins are expressed in various cells, and play crucial roles in cellular metabolism, apoptosis, and aging. FOXO1-null mice exhibit embryonic lethality due to impaired endothelial cell (EC) maturation and vascular remodeling. However, FOXO1-mediated genome-wide regulation in ECs remains unclear. Here, we demonstrate that VEGF dynamically regulates FOXO1 cytosol-nucleus translocation. FOXO1 re-localizes to the nucleus via PP2A phosphatase. RNA-seq combined with FOXO1 overexpression/knockdown in ECs demonstrated that FOXO1 governs the VEGF-responsive tip cell-enriched genes, and further inhibits DLL4-NOTCH signaling. Endogenous FOXO1 ChIP-seq revealed that FOXO1 binds to the EC-unique tip-enriched genes with co-enrichment of EC master regulators, and the condensed chromatin region as a pioneer factor. We identified new promoter/enhancer regions of the VEGF-responsive tip cell genes regulated by FOXO1: ESM1 and ANGPT2. This is the first study to identify cell type-specific FOXO1 functions, including VEGF-mediated tip cell definition in primary cultured ECs.

Keywords: Cell biology; Molecular biology.