Fli1+ cells transcriptional analysis reveals an 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

1 Scopus citations

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 RNAsequencing analysis of non-fli1 expressing cells (fli1-) with these two (fli1+) cell populations,we identified several up-regulated genes, not previously recognized as important, during endothelial development. Compared with fli1- A nd low-fli1+ cells, high-fli1+ cells showed up-regulated expression of the zinc finger transcription factor PRDIBF1 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 impaired their differentiation and migration in vitro. Moreover, zebrafish mutants (mut) with loss of function for the oncogene LIM domain only 2 (lmo2) also showed reduced prdm16 gene expression combined with impaired angiogenesis. Prdm16 expression was reduced further in endothelial (CD31+) cells compared with CD31-cells isolated from lmo2-mutants (lmo2-mut) embryos. Chromatin immunoprecipitation-PCR demonstrated that Lmo2 binds to the promoter and directly regulates the transcription of prdm16. This work unveils a mechanism by which prdm16 expression is activated in endothelial cells by Lmo2 and highlights a possible therapeutic pathway by which to modulate endothelial cell growth and repair.

Original languageEnglish (US)
Article numbere2008559118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number31
DOIs
StatePublished - Aug 3 2021

Keywords

  • Angiogenesis
  • Differentiation
  • Endothelial cells
  • Epigenetic factors
  • Zebrafish

ASJC Scopus subject areas

  • General

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