PRDM6 is enriched in vascular precursors during development and inhibits endothelial cell proliferation, survival, and differentiation

Yaxu Wu, James E. Ferguson, Hong Wang, Rusty Kelley, Rongqin Ren, Holly McDonough, James Meeker, Peter C. Charles, Hengbin Wang, Cam Patterson

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The mechanisms that regulate the differentiation program of multipotential stem cells remain poorly understood. In order to define the cues that delineate endothelial commitment from precursors, we screened for candidate regulatory genes in differentiating mouse embryoid bodies. We found that the PR/SET domain protein, PRDM6, is enriched in flk1(+) hematovascular precursor cells using a microarray-based approach. As determined by 5′ RACE, full-length PRDM6 protein contains a PR domain and four Krüppel-like zinc fingers. In situ hybridization in mouse embryos demonstrates staining of the primitive streak, allantois, heart, outflow tract, paraaortic splanchnopleura (P-Sp)/aorto-gonadal-mesonephric (AGM) region and yolk sac, all sites known to be enriched in vascular precursor cells. PRDM6 is also detected in embryonic and adult-derived endothelial cell lines. PRDM6 is co-localized with histone H4 and methylates H4-K20 (but not H3) in vitro and in vivo, which is consistent with the known participation of PR domains in histone methyltransferase activity. Overexpression of PRDM6 in mouse embryonic endothelial cells induces apoptosis by activating caspase-3 and inducing G1 arrest. PRDM6 inhibits cell proliferation as determined by BrdU incorporation in endothelial cells, but not in rat aortic smooth muscle cells. Overexpression of PRDM6 also results in reduced tube formation in cultured endothelial cells grown in Matrigel. Taken together, our data indicate that PRDM6 is expressed by vascular precursors, has differential effects in endothelial cells and smooth muscle cells, and may play a role in vascular precursor differentiation and survival by modulating local chromatin-remodeling activity within hematovascular subpopulations during development.

Original languageEnglish (US)
Pages (from-to)47-58
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume44
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

Fingerprint

Blood Vessels
Cell Differentiation
Cell Survival
Endothelial Cells
Cell Proliferation
Smooth Muscle Myocytes
Allantois
Primitive Streak
Embryoid Bodies
Yolk Sac
Chromatin Assembly and Disassembly
Zinc Fingers
Bromodeoxyuridine
Regulator Genes
Caspase 3
Histones
In Situ Hybridization
Cues
Cultured Cells
Stem Cells

Keywords

  • Endothelium
  • PR domain
  • Proliferation
  • Stem cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

PRDM6 is enriched in vascular precursors during development and inhibits endothelial cell proliferation, survival, and differentiation. / Wu, Yaxu; Ferguson, James E.; Wang, Hong; Kelley, Rusty; Ren, Rongqin; McDonough, Holly; Meeker, James; Charles, Peter C.; Wang, Hengbin; Patterson, Cam.

In: Journal of Molecular and Cellular Cardiology, Vol. 44, No. 1, 01.2008, p. 47-58.

Research output: Contribution to journalArticle

Wu, Yaxu ; Ferguson, James E. ; Wang, Hong ; Kelley, Rusty ; Ren, Rongqin ; McDonough, Holly ; Meeker, James ; Charles, Peter C. ; Wang, Hengbin ; Patterson, Cam. / PRDM6 is enriched in vascular precursors during development and inhibits endothelial cell proliferation, survival, and differentiation. In: Journal of Molecular and Cellular Cardiology. 2008 ; Vol. 44, No. 1. pp. 47-58.
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AU - McDonough, Holly

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AB - The mechanisms that regulate the differentiation program of multipotential stem cells remain poorly understood. In order to define the cues that delineate endothelial commitment from precursors, we screened for candidate regulatory genes in differentiating mouse embryoid bodies. We found that the PR/SET domain protein, PRDM6, is enriched in flk1(+) hematovascular precursor cells using a microarray-based approach. As determined by 5′ RACE, full-length PRDM6 protein contains a PR domain and four Krüppel-like zinc fingers. In situ hybridization in mouse embryos demonstrates staining of the primitive streak, allantois, heart, outflow tract, paraaortic splanchnopleura (P-Sp)/aorto-gonadal-mesonephric (AGM) region and yolk sac, all sites known to be enriched in vascular precursor cells. PRDM6 is also detected in embryonic and adult-derived endothelial cell lines. PRDM6 is co-localized with histone H4 and methylates H4-K20 (but not H3) in vitro and in vivo, which is consistent with the known participation of PR domains in histone methyltransferase activity. Overexpression of PRDM6 in mouse embryonic endothelial cells induces apoptosis by activating caspase-3 and inducing G1 arrest. PRDM6 inhibits cell proliferation as determined by BrdU incorporation in endothelial cells, but not in rat aortic smooth muscle cells. Overexpression of PRDM6 also results in reduced tube formation in cultured endothelial cells grown in Matrigel. Taken together, our data indicate that PRDM6 is expressed by vascular precursors, has differential effects in endothelial cells and smooth muscle cells, and may play a role in vascular precursor differentiation and survival by modulating local chromatin-remodeling activity within hematovascular subpopulations during development.

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