Journal of Dermatology 2013; 40: 4853

doi: 10.1111/1346-8138.12000

ORIGINAL ARTICLE

Transcriptional regulatory network for psoriasis

Xiaonian LU, Juan DU, Jun LIANG, Xiaohua ZHU, Yongsheng YANG, Jinhua XU
Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China

ABSTRACT
Psoriasis is a common, chronic, intractable skin disease that affects approximately 2% of the worlds population.
Transcriptional regulation is one of the most fundamental processes in psoriasis. However, high-throughput functional analysis of multiple transcription factors and their target genes in psoriasis is still rare. Thus, the objective
of our study was to interpret the mechanisms of psoriasis through the regulation network construction using the
GSE14905 microarray data. The results showed E2F transcription factor 1 (E2F1), jun proto-oncogene (JUN),
nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-jB1), signal transducer and activator of
transcription 1 (STAT1), STAT3 and SP3 were hinge points in our transcriptome network. Importantly, JUN may
regulate activating transcription factor 3 expression to involve cell proliferation process; STAT1 and STAT3 can
inhibit tissue inhibitor of metalloproteinases-3 expression to modulate the cell adhesion molecule pathway; NF-jB
and E2F1 can downregulate cyclin D1, but upregulate proliferating cell nuclear antigen expression to promote the
cell cycle pathway. In addition, the regulation network between transcription factors and pathways revealed that
NF-jB1 could promote the Toll-like receptor signaling pathway and that SP3 may inhibit the steroid hormone biosynthesis pathway in psoriasis. This transcriptional regulation analysis may provide a better understanding of
molecular mechanism and some potential therapeutic targets in the treatment of human psoriasis.

Key words:

gene expression, gene regulation, psoriasis, transcriptome network.

INTRODUCTION
Psoriasis is a chronic autoimmune disease of skin. It occurs
when the immune system sends out faulty signals that speed up
the growth cycle of skin cells. There are five types of psoriasis:
plaque, guttate, inverse, pustular and erythrodermic. The most
common form, plaque psoriasis, typically has raised red or white
scaly skin lesions with a thickened acanthotic epidermis.1
Two mechanisms are thought to contribute to psoriasis. The
first considers psoriasis as primarily an epidermal imbalance
between proliferation and differentiation. The large, silvery
scales observed in the lesions are a consequence of altered
differentiation (hyper- and parakeratosis), whereas thickening
of the epidermis is due to a strongly increased pool of
proliferating keratinocytes. Altered differentiation of psoriatic
keratinocytes is characterized by downregulation of the late
keratinocyte differentiation markers (such as filaggrin, loricrin
and caspase-14), and upregulation of the early differentiation
markers (involucrin and small proline-rich proteins). Differentiation of epidermal cells is controlled by Notch and Wnt signaling
pathways, and by the transcription factors peroxisome proliferator-activated receptor (PPAR)-a, activator protein 2 (AP2) and

cytoplasmic polyadenylation element binding protein 1 (CEBP).

Proliferation of epidermal stem cells are maintained by tumor
protein p63, v-myc myelocytomatosis viral oncogene homolog
(avian) (MYC), integrin-b1 (ITGB1) and transforming growth factor (TGF)-a signaling pathway, and negatively regulated by
TGF-b signaling. Signaling through insulin-like growth factor
receptor and epidermal growth factor receptor also can regulate proliferative behavior in the epidermis. In general, there is
a complex regulatory network in lesional psoriatic skin.2 The
second hypothesis takes the psoriasis as being an innate and
adaptive immune-mediated disorder. T cells become active,
migrate to the dermis, and trigger the release of cytokines
which cause inflammation and the rapid production of skin
cells. Examples of abnormalities in psoriasis are the increased
expression of antimicrobial peptides, activation of type I interferon (IFN) system, and dysregulation of the expression of
cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis
factor (TNF)-a.3
DNA microarray analysis as a global approach has been
widely used to investigate physiological mechanisms in health
and disease.4 A high-throughput microarray experiment has
also been designed to analyze genetic expression patterns and

Correspondence: Jinhua Xu, Ph.D., Department of Dermatology, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai
200040, China. Email: jinhuaxujhx@hotmail.com
Author contribution: Xiaonian Lu and Juan Du are joint first authors of this study.
Conflict of interest: none.
Received 26 June 2012; accepted 24 August 2012.

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A regulation network for psoriasis

identify potential genes to target for psoriasis.5 However, highthroughput functional analysis of multiple transcription factors
and their target genes in psoriasis is still rare. Therefore, the
objective of this study was to identify potential transcription
regulation relationships between transcription factors (TFs) and
differentially expressed genes (DEGs) in psoriasis by using the
microarray data and transcriptional regulation data. In addition,
their underlying molecular mechanisms were also explored by
pathway enrichment analysis.

METHODS
Microarray data
The transcription profile of GSE14905 was obtained from the
National Center for Biotechnology Information Gene Expression
Omnibus (NCBI-GEO; www.ncbi.nlm.nih.gov/geo/), which is
based on the Affymetrix GPL570 platform data (Affymetrix
Human Genome U133 Plus ver. 2.0 Array). A total of 54 chips
were applied, including skin biopsy samples from 21 normal
healthy donors and 33 psoriatic patients (all plaque type).6 All
the donors gave written informed consent.

Regulation network construction

Relationships between TFs and their target DEGs were
matched using regulation data collected from TRANSFAC and
TRED. The regulation network was constructed using Cytoscape software, ver. 2.8.0 (www. cytoscape.org/), with PCC of
more than 0.75 for TFs and their target DEGs.11

Gene ontology (GO) and pathway enrichment

analysis
BiNGO analysis12 was used to identify significantly overrepresented GO biological process. Benjamini and Hochberg multiple-test corrections13 adjusted raw P-values at a significance
level of less than 0.05.
The significant pathway was screened by using an impact
analysis that includes the statistical significance of the set of
pathway genes but also considers other crucial factors such as
the magnitude of each genes expression change, the topology
of the signaling pathway, and their interactions.14 P < 0.05 was
considered statistically significant.

RESULTS

Pathway data

Regulation network construction

Pathway data were collected from the Kyoto Encyclopedia of

Genes and Genomes (KEGG) PATHWAY database (www.genome.jp/kegg/).7 A total of 130 pathways, involving 2287 genes,
were collected from KEGG.

To get pathway-related DEGs of psoriasis, we obtained publicly available microarray GSE14905 datasets from the NCBIGEO. After microarray analysis, the DEGs with fold change of
more than two and P < 0.05 were selected. A total of 2310
genes were selected as DEGs. Based on the significant relationships (PCC > 0.6 or PCC < 0.6) between TFs and their
target genes, 61 putative regulatory relationships were predicted between 18 TFs and 42 target DEGs. By integrating the
regulatory relationships above, a regulation network of psoriasis was built between TFs and their target genes (Fig. 1). In
this network, E2F transcription factor 1 (E2F1), jun proto-oncogene (JUN), nuclear factor of kappa light polypeptide gene
enhancer in B-cells 1 (NF-jB1), ets variant (ETV)4 and signal
transducer and activator of transcription (STAT)1 with higher
degrees formed a local network, suggesting that these TFs
may play an important role in psoriasis. Interestingly, the cyclin
D (CCND)1 target gene was downregulated by peroxisome
proliferator-activated receptor delta (PPARD), STAT3, NF-jB1
and E2F1, but upregulated by Sp3 transcription factor (SP3).
Proliferating cell nuclear antigen (PCNA) was upregulated by
E2F1. In addition, the JUN-mediated activating transcription
factor 3 (ATF3) regulation was activated by FBJ murine osteosarcoma viral oncogene homolog (FOS), early growth response
(EGR1), MYC and v-ets erythroblastosis virus E26 oncogene
homolog 2 (avian) (ETS2).

Regulation data
Regulatory relationship data were obtained from the TRANSFAC public database (www.gene-regulation.com)8 and the
Transcriptional Regulatory Element Database (TRED; http://
rulai.cshl.edu/TRED/).9 A total of 774 pairs of regulatory relationship between 219 TFs and 265 target genes were collected
from TRANSFAC. A total of 5722 pairs of regulatory relationships between 102 TFs and 2920 target genes were collected
from TRED. By combining the two regulation datasets, a total
of 6328 regulatory relationships between 276 TFs and 3002
target genes were ultimately collected.

Differentially expressed genes analysis

The limma method10 was used to identify DEGs in the
GSE14905 dataset. The original expression datasets from all
conditions were processed into expression estimates using the
Robust Multichip Average method with the default settings
implemented in Bioconductor, and then used to construct the
linear model. The DEGs with a fold change of more than two
and of P < 0.05 were selected.

Co-expression analysis
To demonstrate the potential regulatory relationship, Pearsons
correlation coefficient (PCC) was calculated for all pairwise
comparisons of gene-expression values between TFs and the
DEGs. The regulatory relationships in which the absolute PCC
are larger than 0.6 were considered as significant.

2012 Japanese Dermatological Association

GO and pathway enrichment analysis of the

regulation network in psoriasis
Several GO categories were enriched among these genes in
the regulatory network, including response to organic substance, response to endogenous stimulus, response to chemical stimulus and others (Table 1).

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X. Lu et al.

Figure 1. Regulation network between transcription factors (triangles) and differentially expressed genes (DEGs; circles) for psoriasis, constructed using data from TRANSFAC and TRED databases. (?) Stimulation of gene expression; () gene repression.

Table 1. Gene ontology (GO) biological process analysis

GO-ID

Biological process

Counts

P-value

Adjusted
P-value

10033
9719
42221
9725
48518
50896
8284
6355
31323
48522

Response to organic substance

Response to endogenous stimulus
Response to chemical stimulus
Response to hormone stimulus
Positive regulation of biological process
Response to stimulus
Positive regulation of cell proliferation
Regulation of transcription, DNA-dependent
Regulation of cellular metabolic process
Positive regulation of cellular process

21
16
25
15
30
38
15
26
37
27

1.29E-11
8.73E-11
1.44E-10
1.97E-10
2.24E-10
2.92E-10
3.44E-10
2.19E-09
3.56E-09
3.87E-09

1.90E-08
6.42E-08
6.57E-08
6.57E-08
6.57E-08
7.16E-08
7.22E-08
4.02E-07
4.87E-07
4.87E-07

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A regulation network for psoriasis

The significant pathways were also identified, including leukocyte transendothelial migration, cell adhesion molecules, the
PPAR signaling pathway, cell cycle and others (Table 2).

Regulation network between TFs and pathways in

psoriasis
To further investigate the regulatory relationships between TFs
and pathways, we mapped DEGs to pathways and determined
a regulation network between TFs and pathways (Fig. 2). In the
network, FOS, ETS2, EGR1 and NF-jB1 were shown as hub
nodes linked to lots of psoriasis-related pathways. Some TFs
interactively regulated lots of pathways, such as NF-jB1,
STAT1 and CCAAT/enhancer binding protein, delta(CEBPD)
that could regulate the Toll-like receptor (TLR) signaling pathway; SP3 and PPARD both regulated the steroid hormone biosynthesis.

DISCUSSION
Our results represent the comprehensive regulation network of
psoriasis between TFs and target genes and their underlying
molecular pathways. We have shown that the genes E2F1,
JUN, NF-jB1, ETV4 and STAT1 were hub nodes in our transcriptome network. Among them, JUN may regulate ATF3
expression to involve the cell proliferation process; STAT1 and
STAT3 can inhibit tissue inhibitor of metalloproteinases (TIMP)3 expression to modulate the cell adhesion molecule pathway;
NF-jB and E2F1 can downregulate CCND expression, but
upregulate PCNA to promote the cell cycle pathway. In addition, the results of a regulation network between TFs and pathways indicated that NF-jB1 could participate in the TLR
signaling pathway; SP3 may inhibit the steroid hormone biosynthesis pathway.

Table 2. Significant pathway analysis

Pathway name
Leukocyte
transendothelial
migration
Cell adhesion
molecules
Peroxisome
proliferator-activated
receptor signaling
pathway
Cell cycle
Cytokinecytokine
receptor interaction
Vibrio cholerae
infection
DNA replication
Pathways in cancer
Complement and
coagulation cascades
p53 signaling pathway

Impact
factor

Pathway genes
in input (%)

Adjusted
P-value

70.53

15.126

1.66E-29

53.78

14.179

2.39E-22

20.39

31.42

2.97E-08

16.75
13.43

23.72
16.35

9.37E-07
2.11E-05

9.72

17.74

6.43E-04

9.55
8.66
8.08

30.55
13.93
17.39

7.51E-04
0.001663
0.002799

8.02

21.73

0.002966

2012 Japanese Dermatological Association

Jun proto-oncogene encodes a major component of the

heterodimeric transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation and differentiation. C-Jun can be expressed in all the psoriatic skin samples,
but expression is significantly decreased in plaque-type psoriatic skin.15 Inducible epidermal deletion of c-Jun in adult mice
leads to a phenotype resembling the histological and molecular
hallmarks of psoriatic skin.16 In addition, several transient
transfection assays have demonstrated that JUN can form
heterodimers with ATF3 and increases the ATF3 promoter
activity.17 Thus, decreased c-Jun expression in all psoriatic
lesions will lead to reduced ATF3 expression, which also has
been proved in a recent study.18
Signal transducer and activator of transcription-1 and -3 proteins are members of the STAT protein family and they can be
activated by various cytokines and growth factors to regulate
many important biological activities. Microarray analysis of
in vitro-derived macrophages treated with IFN-c shows that
many of the genes upregulated in macrophages are also found
in psoriasis, including STAT1. This indicates that macrophages
are likely to contribute to the pathogenic inflammation in psoriasis skin.19 Transgenic mice with keratinocytes expressing a constitutively active Stat3 can develop psoriasis-like skin lesions.20
Stat3 is also positively stained in human psoriasis samples.21,22
Thus, targeting Stat3 could be useful in ameliorating human psoriatic lesions.23 TIMP3 is a member of a family of endogenous
matrix metalloproteinase (MMP) inhibitor. MMP have been associated with the remodeling of the extracellular matrix and are
abundantly expressed in macrophages and neutrophils of psoriatic lesions.24 TIMP3 is downregulated in psoriatic skin,25 which
may be attributable to upregulated STAT3 expression.26,27
Nuclear factor-jB and E2F1 are TFs that play a crucial role
in the control of cell cycle. Nuclear expression of NF-jB is
detected in 66% of psoriatic lesions; this active phosphorylated form is significantly overexpressed in psoriasis in comparison with normal skin.28 Cell survival factors, such as E2F1,
are reported to predominate over other apoptotic factors, such
as p53, in psoriasis. Activation of apoptotic pathways by ultraviolet B is found to be balanced by activation of E2F1 which is
upregulated in response to DNA damage and promotes DNA
repair.29 CCND1 protein belongs to the highly conserved cyclin
family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Altered
expression of cell-cycle regulatory genes involved in the cyclin
D1p16 INK4-pRb pathway may contribute to epidermal hyperproliferation. The mean CCND1 content in psoriasis patients is
significantly greater than that in controls, but p16 is significantly lower than that in controls. Therefore, CCND1 upregulation and p16 downregulation may be suggested as one
pathogenesis of psoriatic skin.30 The cyclin D1 promoter contains multiple regulatory elements (such as E2F1 and NF-jB),
which may play an important role in its regulation.31 In this
study, we found that CCND was downregulated by NF-jB1
and E2F1. PCNA protein is an auxiliary protein of DNA polymerase-5, which appears early in G1 and becomes more abundant in the S phase, thereafter declining during G2/M phases
of the cell cycle. Thus, the positive PCNA staining is commonly

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X. Lu et al.

Figure 2. Regulation network between transcription factors (triangles) and pathway (box). (?) Stimulation of pathway; () pathway
repression.
used as a marker of keratinocyte proliferation.32 PCNA expression is suppressed by all kinds of anti-psoriatic medicine.33 In
addition, emerging evidence has demonstrated that there is a
positive correlation between E2F1 and PCNA expression.34
Psoriasis is a chronic skin disease that appears to be autoimmune in nature. TLR are known to play an important role in
immune and inflammatory responses of the skin, including psoriasis. For example, in lesional epidermis from psoriatic patients,
TLR2 is more highly expressed on the keratinocytes of the upper
epidermis than on the basal layer, while TLR5 is downregulated
in basal keratinocytes compared with corresponding non-lesional psoriatic epidermis.35 TLR are activated by exogenous (bacterial cell wall components)36 or endogenous (HSP60) ligand
exposure.37 TLR signaling leads to activation of NF-jB through
the adaptor protein MyD88-dependent pathway and induces a

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battery of immune adjuvant effects, which are principally mediated by pro-inflammatory cytokines.38
Steroid hormone therapy is one of the most potent antiinflammatory treatments available for skin conditions including
psoriasis. Steroidogenic acute regulatory protein (StAR) and
metastatic lymph node 64 (MLN64) enzyme are critical components for steroidogenesis. However, studies have reported that
StAR mRNA expression is downregulated in lesional psoriatic
skin39 and MLN64 enzyme expression is also delayed in more
suprabasal layers of lesional psoriatic skin.40 These may be
attributed to transcriptional repression of the StAR promoter by
SP3, CAGA element binding proteins and a co-repressor complex, which is in accordance with our results.41
In conclusion, we have used network analysis as a conceptual framework to explore the pathobiology of psoriasis, based

2012 Japanese Dermatological Association

A regulation network for psoriasis

on the assumption that psoriatic cell behavior is a contextual

attribute of distinct patterns of interactions between multiple
genes. The salient results of our study include many related
transcription factors (such as JUN, STAT1, and NF-jB), target
genes (ATF3, CCND1, and PCNA) and pathways (such as TLR
signaling pathway and steroid hormone biosynthesis). These
results could provide some potential therapeutic targets to
treat psoriasis. However, further experiments are still indispensable to confirm these conclusions.

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