A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature

被引：22

作者：

Kazenwadel, Jan ^{[1
]}

Venugopal, Parvathy ^{[1
,2
]}

Oszmiana, Anna ^{[1
]}

Toubia, John ^{[1
,3
]}

Arriola-Martinez, Luis ^{[1
,2
]}

Panara, Virginia ^{[4
,5
]}

Piltz, Sandra G. ^{[6
,7
,8
]}

Brown, Chris ^{[9
]}

Ma, Wanshu ^{[10
]}

Schreiber, Andreas W. ^{[1
,3
,11
]}

Koltowska, Katarzyna ^{[4
,5
]}

Taoudi, Samir ^{[12
,13
]}

Thomas, Paul Q. ^{[6
,7
,8
]}

Scott, Hamish S. ^{[1
,2
,3
,6
]}

Harvey, Natasha L. ^{[1
,6
]}

机构：

[1] Univ South Australia & SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia

[2] SA Pathol, Dept Genet & Mol Pathol, Adelaide, SA, Australia

[3] Univ South Australia & SA Pathol, Ctr Canc Biol, ACRF Canc Genom Facil, Adelaide, SA, Australia

[4] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden

[5] Uppsala Univ, Beijer Gene & Neuro Lab & Sci Life Labs, Uppsala, Sweden

[6] Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia

[7] South Australian Hlth & Med Res Inst, Genome Editing Program, Adelaide, SA, Australia

[8] Univ Adelaide, South Australian Genome Editing Facil, Adelaide, SA, Australia

[9] Univ South Australia, Adelaide, SA, Australia

[10] Northwestern Univ, Feinberg Cardiovasc Res Inst, Ctr Vasc & Dev Biol, Feinberg Sch Med, Chicago, IL USA

[11] Univ Adelaide, Sch Biol Sci, Adelaide, SA, Australia

[12] Walter & Eliza Hall Inst Med Res, Epigenet & Dev Div, Melbourne, Vic, Australia

[13] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

来源：

NATURE | 2023年 / 614卷 / 7947期

基金：

澳大利亚国家健康与医学研究理事会; 澳大利亚研究理事会;

关键词：

BLOOD-CELLS; STEM-CELLS; EXPRESSION; GENE; VESSELS; GATA2; PROLIFERATION; MAINTENANCE; PROGENITORS; MATURATION;

D O I：

10.1038/s41586-022-05650-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development(1-3). Here we describe a novel enhancer element that is important for regulating the expression of Prox1 in lymphatic endothelial cells. This evolutionarily conserved enhancer is bound by key lymphatic transcriptional regulators including GATA2, FOXC2, NFATC1 and PROX1. Genome editing of the enhancer to remove five nucleotides encompassing the GATA2-binding site resulted in perinatal death of homozygous mutant mice due to profound lymphatic vascular defects. Lymphatic endothelial cells in enhancer mutant mice exhibited reduced expression of genes characteristic of lymphatic endothelial cell identity and increased expression of genes characteristic of haemogenic endothelium, and acquired the capacity to generate haematopoietic cells. These data not only reveal a transcriptional enhancer element important for regulating Prox1 expression and lymphatic endothelial cell identity but also demonstrate that the lymphatic endothelium has haemogenic capacity, ordinarily repressed by Prox1.

引用

页码：343 / +

页数：23