Mel-18, a mammalian Polycomb gene, regulates angiogenic gene expression
of endothelial cells
, Hyun-Jung Choi
, Yong-Sun Maeng
, Jung-Yeon Choi
, Minhyung Kim
, Ja-Young Kwon
, Young-Myeong Kim
, Daehee Hwang
, Young-Guen Kwon
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea
Department of Obstetrics and Gynecology, College of Medicine, Yonsei University, Seoul, Republic of Korea
Vascular system research center, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea
Received 17 August 2010
Available online 27 August 2010
Polycomb group gene
Mel-18 is a mammalian homolog of Polycomb group (PcG) genes. Microarray analysis revealed that Mel-
18 expression was induced during endothelial progenitor cell (EPC) differentiation and correlates with
the expression of EC-speciﬁc protein markers. Overexpression of Mel-18 promoted EPC differentiation
and angiogenic activity of ECs. Accordingly, silencing Mel-18 inhibited EC migration and tube formation
in vitro. Gene expression proﬁling showed that Mel-18 regulates angiogenic genes including kinase insert
domain receptor (KDR), claudin 5, and angiopoietin-like 2. Our ﬁndings demonstrate, for the ﬁrst time,
that Mel-18 plays a signiﬁcant role in the angiogenic function of ECs by regulating endothelial gene
Ó 2010 Elsevier Inc. All rights reserved.
Neovascularization, an essential process in embryonic develop-
ment and adult pathophysiology, occurs through complicated pro-
cesses involving vasculogenesis and angiogenesis. Angiogenesis
relies on the sprouting and co-option of proliferating endothelial
cells (ECs) from the adjacent pre-existing vascular bed, whereas
vasculogenesis is the de novo formation of blood vessels from
angioblasts during development and from endothelial precursor
cells (EPCs) derived from bone marrow, peripheral blood, and cord
blood in adults . Although ECs can be differentiated from EPCs,
phenotypic and functional differences exist between EPCs and
ECs, possibly due to massive genetic changes including gene silenc-
ing and activation. Numerous studies have demonstrated the tran-
scriptional regulatory mechanisms of genes involved in endothelial
function, which may also be essential in differentiating EPCs to
functioning ECs .
Polycomb group (PcG) genes were ﬁrst identiﬁed in Drosophila
as regulators of homeobox (HOX) genes for body patterning during
development [3,4]. In adults, PcG genes also play important regu-
latory roles in processes such as cell proliferation, senescence,
and tumorigenesis . PcG genes interact to form multimeric pro-
tein complexes, called Polycomb repressive complexes (PRCs).
Mel-18 (Polycomb group ring ﬁnger protein 2 [PCGF2]) is a mam-
malian homolog of the Drosophila posterior sex comb (Psc) protein
of the PRC1 complex. The mammalian PRC1-like complex also con-
tains CBX2 (M33), BMI1, PHC1 (RAE28), RING1A, and RNF2
(RING1B). PRC1, cooperating with PRC2, has been reported to inter-
act with chromatin–remodeling complexes, DNA-binding factors
or modiﬁed histones to alter chromatin structure . Most studies
have described the gene silencing mechanism of PcG complexes; to
our knowledge, its involvement in gene activation or mammalian
cell differentiation has rarely been reported.
Mutations in mouse PRC1 proteins cause transformation of the
axial skeleton and various hematopoietic and neurological abnor-
malities. For example, Mel-18 mutant mice showed defects in
anterior–posterior axis formation and lymphocyte differentiation
[6,7]. Of particular interest, Th2 cell differentiation was impaired
and GATA3 induction was reduced in activated CD4 T cells of
Mel-18-/- mice; the introduction of GATA3 rescued the impaired
Th2 cell differentiation . Mel-18 deﬁciency also resulted in dys-
regulation of self-renewal and cell cycle status of hematopoietic
stem cells (HSCs) . Despite the intimate relationship between
hematopoietic and endothelial cells, the role of Mel-18 in ECs has
not been determined.
Accumulating evidence indicates that PcG genes play a critical
role in the differentiation of progenitors to speciﬁc cell lineage
and maintenance of cell identity; however, their roles in EC-spe-
0006-291X/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
Corresponding author. Address: Department of Biochemistry, College of Life
Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Fax: +82 2 362 9897.
E-mail address: firstname.lastname@example.org (Y.-G. Kwon).
These authors contributed equally to this work.
Biochemical and Biophysical Research Communications 400 (2010) 523–530
Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications
journal homepage: www.elsevier.com/locate/ybbrc