PMID- 34330825 OWN - NLM STAT- MEDLINE DCOM- 20211207 LR - 20221005 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 31 DP - 2021 Aug 3 TI - Fli1(+) cells transcriptional analysis reveals an Lmo2-Prdm16 axis in angiogenesis. LID - 10.1073/pnas.2008559118 [doi] LID - e2008559118 AB - A network of molecular factors drives the development, differentiation, and maintenance of endothelial cells. Friend leukemia integration 1 transcription factor (FLI1) is a bona fide marker of endothelial cells during early development. In zebrafish Tg(fli1:EGFP)(y1) , we identified two endothelial cell populations, high-fli1(+) and low-fli1(+), by the intensity of green fluorescent protein signal. By comparing RNA-sequencing analysis of non-fli1 expressing cells (fli1(-)) with these two (fli1(+)) cell populations, we identified several up-regulated genes, not previously recognized as important, during endothelial development. Compared with fli1(-) and low-fli1(+) cells, high-fli1(+) cells showed up-regulated expression of the zinc finger transcription factor PRDI-BF1 and RIZ homology domain containing 16 (prdm16). Prdm16 knockdown (KD) by morpholino in the zebrafish larva was associated with impaired angiogenesis and increased number of low-fli1(+) cells at the expense of high-fli1(+) cells. In addition, PRDM16 KD in endothelial cells derived from human-induced pluripotent stem cells impaired their differentiation and migration in vitro. Moreover, zebrafish mutants (mut) with loss of function for the oncogene LIM domain only 2 (lmo2) also showed reduced prdm16 gene expression combined with impaired angiogenesis. Prdm16 expression was reduced further in endothelial (CD31(+)) cells compared with CD31(-) cells isolated from lmo2-mutants (lmo2-mut) embryos. Chromatin immunoprecipitation-PCR demonstrated that Lmo2 binds to the promoter and directly regulates the transcription of prdm16 This work unveils a mechanism by which prdm16 expression is activated in endothelial cells by Lmo2 and highlights a possible therapeutic pathway by which to modulate endothelial cell growth and repair. FAU - Matrone, Gianfranco AU - Matrone G AUID- ORCID: 0000-0001-7084-3546 AD - Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030; gianfranco.matrone@ed.ac.uk. AD - British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. FAU - Xia, Bo AU - Xia B AD - Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030. FAU - Chen, Kaifu AU - Chen K AD - Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030. FAU - Denvir, Martin A AU - Denvir MA AD - British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. FAU - Baker, Andrew H AU - Baker AH AUID- ORCID: 0000-0003-1441-5576 AD - British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom. FAU - Cooke, John P AU - Cooke JP AUID- ORCID: 0000-0003-0033-9138 AD - Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030. LA - eng GR - WT103782AIA/BHF_/British Heart Foundation/United Kingdom GR - R01 HL133254/HL/NHLBI NIH HHS/United States GR - RM/17/3/33381/BHF_/British Heart Foundation/United Kingdom GR - R01 GM125632/GM/NIGMS NIH HHS/United States GR - RG/16/10/32375/BHF_/British Heart Foundation/United Kingdom GR - R01 HL148338/HL/NHLBI NIH HHS/United States GR - CH/09/002/BHF_/British Heart Foundation/United Kingdom GR - RE/13/3/30183/BHF_/British Heart Foundation/United Kingdom GR - RE/18/5/34216/BHF_/British Heart Foundation/United Kingdom GR - CH/11/2/28733/BHF_/British Heart Foundation/United Kingdom GR - WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (DNA-Binding Proteins) RN - 0 (Platelet Endothelial Cell Adhesion Molecule-1) RN - 0 (Proto-Oncogene Protein c-fli-1) RN - 0 (Zebrafish Proteins) RN - 0 (prdm16 protein, zebrafish) RN - 147336-22-9 (Green Fluorescent Proteins) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Cell Differentiation MH - DNA-Binding Proteins/genetics/*metabolism MH - Embryo, Nonmammalian MH - Endothelial Cells/*physiology MH - Gene Expression Regulation, Developmental MH - Green Fluorescent Proteins/genetics/metabolism MH - Humans MH - Induced Pluripotent Stem Cells/*physiology MH - Neovascularization, Physiologic/*physiology MH - Platelet Endothelial Cell Adhesion Molecule-1/genetics/metabolism MH - Proto-Oncogene Protein c-fli-1/*physiology MH - RNA-Seq MH - Transcriptome MH - Up-Regulation MH - Zebrafish MH - Zebrafish Proteins/genetics/*metabolism PMC - PMC8346798 OTO - NOTNLM OT - angiogenesis OT - differentiation OT - endothelial cells OT - epigenetic factors OT - zebrafish COIS- The authors declare no competing interest. EDAT- 2021/08/01 06:00 MHDA- 2021/12/15 06:00 PMCR- 2022/01/30 CRDT- 2021/07/31 06:30 PHST- 2021/07/31 06:30 [entrez] PHST- 2021/08/01 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2022/01/30 00:00 [pmc-release] AID - 2008559118 [pii] AID - 202008559 [pii] AID - 10.1073/pnas.2008559118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2008559118. doi: 10.1073/pnas.2008559118.