Abstract
Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development1,2,3. 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.
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Data availability
The datasets and material generated during the current study are available from the corresponding author on reasonable request (N.L.H.). GATA2 ChIP–seq data have been deposited in the European Nucleotide Archive under accession number PRJEB9436. PROX1, FOXC2 and NFATC1 ChIP–seq and human LEC and BEC RNA-seq data have been submitted to the Gene Expression Omnibus (GEO) under accession number GSE129634. Mouse LEC (pre-OP9 or post-OP9) RNA-seq and mouse LEC and BEC microarray data have been submitted to the GEO under accession number GSE184046. The HE and E RNA-seq data used for GSEA (Fig. 4) were generated in a published study31 and were obtained from the GEO database under the accession number GSE103813. Source data are provided with this paper.
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Acknowledgements
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.
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J.K., H.S.S. and N.L.H. conceived the study. P.V., J.K. and A.O. performed the haematopoiesis assays. V.P. and K.K. designed, generated and assessed transgenic zebrafish. S.G.P. and P.Q.T. advised on design and generated transgenic and genome-edited mice. C.B. analysed mouse phenotypes. W.M. generated and provided Prox1+/GFP-Cre embryos. J.K. performed ChIP, ChIP–seq and RNA-seq experiments and assessed mouse lymphatic phenotypes. J.K., J.T., L.A.-M. and A.W.S. analysed the bioinformatic data. S.T. advised on embryonic haematopoiesis assays. J.K. and N.L.H. wrote the manuscript. All authors edited and approved the manuscript.
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Extended data figures and tables
Extended Data Fig. 1 The Prox1 −11kb enhancer drives reporter gene expression in lymphatic endothelial cells and at high levels in valves.
a, ChIP in hLECs demonstrates binding of GATA2, FOXC2, NFATC1 and PROX1 at the Prox1 −11 kb enhancer and promoter regions. Data are independent experiments and shown as mean ± SEM when n > 2. b, Schematic of construct used to generate stable transgenic reporter mice. c, Strategy for CRISPR-Cas9 mediated deletion of the Prox1 −11 kb element. Guide RNA sequence targeting GATA2 binding site (underlined) and resulting 5 bp deletion are indicated. d, CRISPR-Cas9 mediated deletion series. e, Immunofluorescent analysis of mouse embryos carrying the Prox1 −11 kb enhancer driven lacZ reporter transgene. Transverse sections at E11.5 show β-galactosidase activity is detected in PROX1+ endothelial cells lining the cardinal vein (arrowheads). Coronal sections in the jugular region at E12.5 and E14.5, reveal high levels of reporter activity in lymphovenous valves (arrows) while there is no detectable reporter gene expression in PROX1+ hepatocytes in E14.5 liver. f, Wholemount X-gal staining of tissues from transgenic mouse pups at post-natal day 4. β-galactosidase activity is present in the lung, dermis, thoracic duct, and mesenteric lymphatic vasculature. In lymphatic vasculature at early post-natal stages, reporter activity is restricted to larger collecting vessels and is not observed in lymphatic vessels in tissues analysed by wholemount X-gal staining at adult stages >P28. Black arrows indicate valves; left side (LS); right side (RS). g, The Prox1 −11 kb enhancer drives reporter gene expression in venous and cardiac valves. Transverse sections of transgenic mouse embryos at E18.5 show reporter activity in venous valves (arrows), semilunar and atrioventricular cardiac valves. Scale bars, 100 µm (e, g), 200 µm (f).
Extended Data Fig. 2 Enhancer driven reporter activity in zebrafish.
a, At 5 days post-fertilization (dpf) zebrafish reporter lines for the zebrafish −2.1 kb prox1a and mouse −11 kb Prox1 enhancer elements drive GFP expression (cyan) in the facial lymphatic endothelium (arrowheads), including the facial valve (arrow) as demonstrated by overlapping expression with Tg(−5.2lyve1b:DsRed2)nz101 or TgBAC(prox1a:KalTA4-4xUAS-ADV.E1b:TagRFP)nim5 (both magenta). b, In both enhancer reporter lines at 5dpf, endothelial GFP signal (cyan) is restricted to the lymphatic vessels in the face, as shown by lack of co-expression with Tg(kdr-l:ras-cherry)s916, which marks the venous endothelium of the primary head sinus (magenta). Additional domains of non-endothelial expression in the face appear to be induced ectopically by both enhancers. c, At 54 h post-fertilization, after sprouting of the facial lymphatics has commenced, co-expression of mouse enhancer-driven GFP (cyan) with lyve1b is observed in the lymphatic progenitors coming from two venous niches, the common cardinal vein lymphangioblasts (CCV-L, arrowhead) and the primary head sinus lymphangioblasts (PHS-LP, arrow). Asterisk indicates co-expression in the underlying PHS. Scale bars, 50 µm.
Extended Data Fig. 3 Oedema and lymphatic vascular defects are similar in mutant embryos with a 1068 bp or 5 bp deletion of the Prox1 −11 kb enhancer.
a, Ventral view illustrating jugular oedema in enhancer mutant compared with wildtype littermate. b, Mutant and wild type littermates at E14.5. Arrowheads indicate subcutaneous oedema. Oedema was observed in 17% (6/35) of homozygous E14.5 Prox1 −11 kbΔ5/Δ5 embryos and 11.7% (7/60) of heterozygous E14.5 Prox1 −11 kb+/Δ5 embryos. c, Compared with wildtype littermates, mutant embryos exhibit enlarged jugular lymph sacs and dilated dermal lymphatic vessels (arrows) in the absence of overt oedema. d, E17.5 embryos subjected to wholemount immunostaining of skins and mesenteries in Fig. 2f, g. showing the region of dermis used for staining. Blood filled vessels in the region of the axilla are indicated (arrow). Scale bars, 400 µm.
Extended Data Fig. 4 The Prox1 −11 kb enhancer controls Prox1 mRNA levels in lymphatic endothelial cells.
a, Prox1 mRNA levels in E18.5 primary dermal LECs and BECs. Data represent individual litters (5–7 embryos) of each genotype and are shown as mean values ± SD (n = 3 replicates for each litter). b, Prox1 mRNA levels in livers isolated from embryos of each genotype at E18.5. Data shown as mean ± SD, unpaired two-tailed t test with no adjustment for multiple comparisons. c, Immunostaining of liver sections taken from embryos at E14.5 show no differences in PROX1 levels (red). d, Reduction of Prox1 mRNA in LECs (*P = 0.02310) is accompanied by reduced Flt4 (*P = 0.01706) and increased CD34 expression (*P = 0.01705). Data represent average expression in LECs from three independent litters and are shown as mean ± SEM., unpaired two-tailed t test with no adjustment for multiple comparisons. e, Immunostaining of coronal sections of E14.5 embryos demonstrates reduced levels of PROX1 (magenta), LYVE1 (yellow) and VEGFR3 (cyan) in lymphovenous valves (arrows) of mutant embryos compared with wild type littermates. f, Runx1 and Gata2 mRNA levels in primary dermal LECs and BECs isolated at E18.5. Data represent average expression from three independent litters and are shown as mean values ± SEM. *P = 0.0101, ordinary one-ANOVA with Dunnett’s multiple comparisons (where error bars are not shown n = 2). Scale bars, 100 µm (c, e).
Extended Data Fig. 5 Transcriptomic analysis of lymphatic endothelial cells indicates a shift in identity of enhancer mutant LECs towards that of blood endothelial cells.
a, Differential gene expression in RNA-seq analysis of LECs isolated from mutant and wildtype embryos at E14.5. Selected genes are ranked in order of expression level in wildtype (highest to lowest, left to right) with markers of LEC identity (red) and BEC identity (blue) highlighted. b, Heatmap comparing microarray analysis of E14.5 LEC and BEC RNA with RNA-seq data shows genes up-regulated in enhancer mutant LECs correlate with genes expressed at higher levels in BECs and vice versa. Green bars indicate genes with a positive correlation to a shift in identity of LEC to BEC in mutant versus wildtype. A Fisher’s Exact Test shows the association between microarray and RNA-seq outcomes is significant, two-tailed p value < 0.0001.
Extended Data Fig. 6 Deletion of the GATA site ablates binding of PROX1, FOXC2 and NFATC1 to the Prox1 −11 kb enhancer.
a, ChIP assays using primary LECs isolated from mutant embryos at E17.5 show no enrichment over IgG control when the GATA2 site is absent. b, Model proposing that GATA2 acts as a pivotal factor at the Prox1 −11 kb enhancer to promote recruitment of transcriptional componentry responsible for driving Prox1 expression in LECs. c, Quantification of interaction frequency of the Prox1 −11 kb enhancer with the Prox1 promoter in cultured human LEC. Chromosome Conformation and Capture (3C) analysis of regions proximal to the Prox1 gene demonstrates increased interaction frequency relative to a BAC control, of the anchor fragment (containing the promoter) and fragments X (containing the enhancer) and XII. Data are shown as mean values ± SD, n = 3. Primer sequences and quantification are available in Source Data Extended Data Fig. 6.
Extended Data Fig. 7 Cell clusters in the jugular lymph sacs of Prox1 enhancer mutant mice express range of hematopoietic and endothelial markers.
a, Coronal sections of E14.5 mutant embryos illustrating cells within clusters budding from PROX1+ LYVE1+ CD31+VECAD+ lymphatic endothelium are heterogenous in identity and are variously positive for RUNX1, cKIT, CD45, GATA2 and CD34. Data are representative of clusters observed in 7 of 15 embryos analyzed at E14.5. b, Rare, small clusters were also observed budding from the jugular lymph sacs of wildtype embryos at E14.5. These clusters are positive for RUNX1, cKIT and CD45. A CD45+ VECAD+ PROX1+ cell is indicated (arrow). Data are representative of two independent embryos. JLS, jugular lymph sac. Scale bars, 50 µm.
Extended Data Fig. 8 Gating strategies used for sorting and characterization of lymphatic and haemogenic endothelial cells.
a, Dorso-anterior regions of E14.5 embryos from wildtype (+/+) or homozygous mutant (Δ/Δ) litters were dissected as indicated, taking care to remove liver, lungs hearts and thymus. 6–8 torsos from a single litter were pooled and digested to generate a single cell suspension. Following F480+ Lin+ depletion, FACS sorted CD45-LYVE1+VECAD+ cells were plated on OP9 feeder layers with cytokines for 7 days. In the case of transcriptomic analyses (Extended Data Figs. 5a,b, 10a), half of the cells from each genotype were processed for RNA (pre-OP9) while the other half were grown on OP9 and then sorted to purify LYVE1+VECAD+ cells (post-OP9). For methylcellulose colony assays all CD45+ cells were FACS purified from OP9 co-cultures, plated into Methocult and cultured for 9–14 days (Fig. 4a). Colonies were enumerated and harvested for FACS analysis (Fig. 4b and Extended Data Fig. 9a). b, FACS analysis of colonies arising after 14 days demonstrates differences and overlap between enhancer mutant and wildtype LEC derived colonies. Venn diagram shows percentages of CD45+ cells also positive for CD41, CD16/32 and cKIT in each genotype. Data are representative of 5 independent experiments. c, Methylcellulose colonies derived from wildtype and enhancer mutant LECs have replating capacity. Colonies were harvested 14 days after initial plating, replated in Methocult™ and assessed at d8. Cells from enhancer mutant colonies demonstrate enhanced proliferation. Data are representative of three independent experiments. Scale bars, 200 µm.
Extended Data Fig. 9 Hematopoietic colonies arising from lymphatic endothelial cells express markers characteristic of erythromyeloid progenitor cells which originate from the yolk sac.
a, Cells harvested from methylcellulose cultures and positive for CD45 were assessed by staining with a range of antibodies for hematopoietic markers. Colonies from both wildtype and enhancer mutant LECs include populations of cells positive for CD41, CD16/32 and cKIT, and negative for other markers analysed, except for a small population of Gr1+ cells observed in two litters (D/D litter a; +/+ litter c). b, Multidimensional scaling (MDS) plot of RNA-seq data from wildtype and mutant LECs isolated at E14.5. While both genotypes show similarity prior to co-culture with OP9 cells, RNA sequence analysis reveals a divergent response of the transcriptome of wildtype compared with enhancer mutant LECs post-OP9 culture. c, Comparison of RNA levels (expressed as reads per million) in wildtype and enhancer mutant LEC pre- and post-OP9 culture, demonstrates an increase in Itga2b transcripts in both genotypes, consistent with the levels of CD41 observed in FACS analysis. Expression of Kit is increased in enhancer mutant LEC but decreased in wildtype, which is also reflected in FACS analysis of cKIT levels, while levels of Prox1 are reduced and Runx1 levels are increased in enhancer mutant cells.
Extended Data Fig. 10 Transcriptomic analyses show mutation of the Prox1 −11 kb enhancer results in a shift towards a hemogenic endothelial identity.
a, RNA-seq analysis of genes differentially expressed between mutant and wildtype LECs isolated at E14.5, pre- and post-OP9 coculture. Heatmaps show relative expression of genes identified in gene set enrichment analysis (GSEA) in Fig. 4c. b, Microarray analysis of RNA isolated from wild-type E14.5, E16.5 and E18.5 dermal LEC and BEC shows that LECs express higher levels of hematopoietic and hemogenic endothelial genes than do BECs. Heatmap of gene expression highlighting a selection of genes. Haematopoietic genes are marked in orange while those marked in black are endothelial genes. These data suggest that LECs are poised to acquire hemogenic endothelial cell identity.
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Kazenwadel, J., Venugopal, P., Oszmiana, A. et al. A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature. Nature 614, 343–348 (2023). https://doi.org/10.1038/s41586-022-05650-9
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DOI: https://doi.org/10.1038/s41586-022-05650-9
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