TY - JOUR
T1 - A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature
AU - Kazenwadel, Jan
AU - Venugopal, Parvathy
AU - Oszmiana, Anna
AU - Toubia, John
AU - Arriola-Martinez, Luis
AU - Panara, Virginia
AU - Piltz, Sandra G.
AU - Brown, Chris
AU - Ma, Wanshu
AU - Schreiber, Andreas W.
AU - Koltowska, Katarzyna
AU - Taoudi, Samir
AU - Thomas, Paul Q.
AU - Scott, Hamish S.
AU - Harvey, Natasha L.
N1 - Funding Information:
We thank the staff at the UniSA Core Animal Facility for animal husbandry and D. Lawrence for assistance with initial bioinformatic analyses. This study utilized the Australian Phenomics Network Histopathology and Organ Pathology Service (University of Melbourne) and the South Australian Genome Editing Service (University of Adelaide). Confocal microscopy and flow cytometry were performed at the Detmold Imaging and Flow Cytometry Facility (UniSA). This work was supported by grants from the NHMRC (1061365 and 1146706 to N.L.H. and H.S.S.) and ARC (DP210103351 to N.L.H.). K.K. and V.P. were supported by Wallenberg Fellowships (2017.0144), Vetenskapsådet (VR-MH-2016-01437) and the Kjell and Märta Beijer Foundation. P.V. was supported by a fellowship from Maddie Riewoldt’s Vision (MRV0017). N.L.H. was supported by an ARC Future Fellowship (FT130101254). H.S.S. was supported by an NHMRC Principal Research Fellowship (1023059) and Cancer Council SA’s Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023
Y1 - 2023
N2 - Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development1–3. 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.
AB - Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development1–3. 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.
UR - http://www.scopus.com/inward/record.url?scp=85146839666&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05650-9
DO - 10.1038/s41586-022-05650-9
M3 - Article
AN - SCOPUS:85146839666
JO - Nature
JF - Nature
SN - 0028-0836
ER -