COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1.
Endothelial cell (EC) identity is in part genetically predetermined. Transcription factor NR2F2 (also known as chicken ovalbumin upstream promoter transcription factor II, COUP-TFII) plays a key role in EC fate decision making; however, many of the underlying mechanisms remain enigmatic. In the present study, we demonstrate that NR2F2 differentially regulates gene expression of venous versus lymphatic ECs (LECs) and document a novel paradigm whereby NR2F2 homodimers induce a venous EC fate, while heterodimers with the LEC-specific transcription factor PROX1 instruct LEC lineage specification. NR2F2 homodimers inhibit arterial differentiation in venous ECs through direct binding to the promoter regions of the Notch target genes HEY1 and HEY2 (HEY1/2), whereas NR2F2/PROX1 heterodimers lack this inhibitory effect, resulting at least in part in non-canonical HEY1/2 expression in LECs. Furthermore, NR2F2/PROX1 heterodimers actively induce or are permissive for the expression of a major subset of LEC-specific genes. In addition to NR2F2/PROX1 heterodimerisation, the expression of HEY1 and some of these LEC-specific genes is dependent on PROX1 DNA binding. Thus, NR2F2 homodimers in venous ECs and NR2F2/PROX1 heterodimers in LECs differentially regulate EC subtype-specific genes and pathways, most prominently the Notch target genes HEY1/2. This novel mechanistic insight could pave the way for new therapeutic interventions for vascular-bed-specific disorders.
Department of Cardiovascular Sciences, Molecular and Vascular Biology Research Unit, Endothelial Cell Biology Unit, KU Leuven, B-3000 Leuven, Belgium.
Xabier L
XL
Aranguren
Manu
M
Beerens
Giulia
G
Coppiello
Cornelia
C
Wiese
Ine
I
Vandersmissen
Antonio
A
Lo Nigro
Catherine M
CM
Verfaillie
Manfred
M
Gessler
Aernout
A
Luttun
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D015153:Blotting, Western; D051837:COUP Transcription Factor II / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004730:Endothelium, Vascular / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D042601:Lymphatic Vessels / Q000378:metabolism*; D055503:Protein Multimerization; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014680:Veins / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D051837:COUP Transcription Factor II; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C485631:HEY1 protein, human; C405693:HEY2 protein, human