COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1
COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1
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DOI：
10.1242/jcs.116293
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发表时间：
2013-03-01
影响因子：
4
通讯作者：
Luttun, Aernout
中科院分区：
文献类型：
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作者：
Aranguren, Xabier L.;Beerens, Manu;Luttun, Aernout
内皮细胞（EC）的身份在一定程度上是由基因决定的。转录因子NR2F2（又称鸡卵白蛋白上游启动子转录因子II， COUP-TFII）在EC命运决策中起关键作用；然而，许多潜在的机制仍然是个谜。在本研究中，我们证明了NR2F2对静脉与淋巴ECs （LECs）基因表达的差异调节，并记录了NR2F2同型二聚体诱导静脉EC命运的新范式，而具有LEC特异性转录因子PROX1的异源二聚体指导LEC谱系规范。NR2F2同型二聚体通过直接结合Notch靶基因HEY1和HEY2的启动子区域（HEY1/2）抑制静脉内皮细胞的动脉分化，而NR2F2/PROX1异源二聚体缺乏这种抑制作用，至少在一定程度上导致了内皮细胞中HEY1/2的非典型表达。此外，NR2F2/PROX1异源二聚体积极诱导或允许主要的lec特异性基因子集的表达。除了NR2F2/PROX1异源二聚化外，HEY1和一些lec特异性基因的表达依赖于PROX1 DNA结合。因此，静脉内皮细胞中的NR2F2同型二聚体和内皮细胞中的NR2F2/PROX1异源二聚体对EC亚型特异性基因和通路的调控存在差异，其中以Notch靶基因HEY1/2调控最为显著。这种新颖的机制见解可能为血管床特异性疾病的新治疗干预铺平道路。
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.