FLI1+ cells transcriptional analysis reveals LMO2-PRDM16 axis in angiogenesis

Gianfranco Matrone, Bo Xia, Kaifu Chen, Martin A Denvir, Andrew H Baker, John P Cooke

Research output: Contribution to journalArticlepeer-review

Abstract

A network of molecular factors drives the development, differentiation and maintenance of endothelial cells. Friend leukemia integration 1 transcription factor (FLI1) is a bona fide marker of endothelial cells during early development. In zebrafish Tg(Fli1:EGFP)y1 we identified two endothelial cell populations, high-FLI1+ and low-FLI1+, by the intensity of green fluorescent protein signal. By comparing RNA-Seq analysis of non-FLI1 expressing cells (FLI1-) with these two (FLI1+) cell populations we identified several novel upregulated genes, not previously recognised as important, during endothelial development.
Compared to FLI1 negative (FLI1-) and low-FLI1+ cells, high-FLI1+ cells showed upregulated expression of the zinc finger transcription factor PRDI-BF1 and RIZ homology domain containing 16 (PRDM16). PRDM16 knockdown (KD) by morpholino in the zebrafish larva was associated with impaired angiogenesis and increased number of low- FLI1+ cells at the expense of high-FLI1+ cells. In addition, PRDM16 KD in endothelial cells derived from human induced Pluripotent Stem Cells (iPSC) impaired their differentiation and migration in vitro. Moreover, zebrafish mutants with loss-of-function for the oncogene LIM domain only 2 (LMO2-mut) also showed reduced PRDM16 gene expression combined with impaired angiogenesis. PRDM16 expression was reduced further in endothelial (CD31+) cells compared to CD31- cells isolated from LMO2-mut embryos. ChIP-PCR demonstrated that LMO2 binds to the promoter and directly regulates the transcription of PRDM16. This work unveils a novel mechanism by which PRDM16 expression is activated in endothelial cells by LMO2 and highlights a possible new therapeutic pathway by which to modulate endothelial cell growth and repair.

Original languageEnglish
JournalProceedings of the National Academy of Sciences
DOIs
Publication statusPublished - 3 Aug 2021

Keywords

  • Endothelial cells
  • differentiation
  • FLI1
  • LMO2
  • PRDM16
  • zebrafish

Fingerprint

Dive into the research topics of 'FLI1+ cells transcriptional analysis reveals LMO2-PRDM16 axis in angiogenesis'. Together they form a unique fingerprint.

Cite this