Physiol Genomics 46: 113–122, 2014.
First published December 10, 2013; doi:10.1152/physiolgenomics.00157.2013.
Review
MicroRNAs in normal and psoriatic skin
Jing Xia1,2 and Weixiong Zhang1,2,3
1
Institute for Systems Biology, Jianghan University, Wuhan, Hubei, China; 2Department of Computer Science and
Engineering, Washington University, St. Louis, Missouri; and 3Department of Genetics, Washington University School of
Medicine, St. Louis, Missouri
Submitted 4 October 2013; accepted in final form 6 December 2013
Xia J, Zhang W. MicroRNAs in normal and psoriatic skin. Physiol
Genomics 46: 113–122, 2014. First published December 10, 2013;
doi:10.1152/physiolgenomics.00157.2013.—Psoriasis is a chronic and common
human skin disorder currently with no cure. Psoriatic skin displays inflammatory,
raised, and scaly lesions with widely aberrant gene expression. Recent studies have
revealed critical roles that microRNAs play as a class of posttranscriptional gene
regulator in skin development and skin diseases. A substantial number of novel
microRNAs have been identified in skin, and much has been learned about the
dysregulated expression and functional roles of microRNAs in psoriasis, as well as
the robustness and plasticity of microRNA-mediated gene expression regulation.
Here we review recent progresses in discovery, profiling, and characterization of
microRNAs in human psoriatic skin, discuss insights to their biological functions,
and share our view on remaining challenges to be addressed.
psoriasis; skin development; microRNA; endogenous siRNA
organ of the body; it regenerates
throughout the life of every individual, serves as the outermost
barrier to prevent inner organs from dehydration, is able to
repair when injured through a complex healing process, and
responds to a variety of environmental stress and hazards (25,
54). Skin has developed a system of regulatory mechanisms to
maintain these functions, orchestrated by various mediators
that have local or systemic effects (79 – 81).
As a common skin disease, psoriasis is a chronic, autoimmune, and complex genetic disorder that affects 2⬃3% of the
European population. Psoriatic skin has symptoms of inflammation and raised and scaly lesions (8). Three different types
of cellular alteration occur in psoriatic involved skin: abnormal
differentiation of keratinocyte, hyperproliferation of keratinocyte, and infiltration of immune cells (70). Much has been
learned about the molecular components and cellular pathways
of inflammation that contribute to the pathogenesis of psoriasis
(30, 55, 107), as well as genetic and environmental factors that
influence the onset and progression of psoriasis (35, 71).
Results from recent studies have indicated that microRNAs
(miRNAs), as a novel regulator of gene expression, play
important roles in psoriasis. miRNAs form a class of short,
nonprotein-coding, regulatory RNAs that play critical roles in
nearly all biological processes, including cell differentiation,
development, and metabolism, as well as complex diseases (6,
12). The maturation of miRNAs involves multiple steps, during
which two intermediate forms of miRNAs, primary (pri-) and
precursor (pre-)miRNAs, are produced sequentially. In this
process, RNase III enzyme Drosha and partner double-stranded
RNA (dsRNA) binding protein Dgcr8 cleave pri-miRNAs to
HUMAN SKIN IS THE LARGEST
Address for reprint requests and other correspondence: W. Zhang, Dept. of
Computer Science and Engineering, Washington Univ. in St. Louis, 1 Brookings Dr., St. Louis, MO 63130 (e-mail: [email protected]).
produce hairpin-shaped pre-miRNAs that are recognized by
Exportin5 and are subsequently transported from nucleus to
cytoplasm. There, another RNase III enzyme Dicer cleaves the
pre-miRNAs to release ⬃22 nucleotide (nt) dsRNA duplexes,
namely miRNA/miRNA* duplexes, with ⬃2 nt 3= overhangs.
One strand of a RNA duplex, termed mature miRNA, is then
loaded into an Argonaute protein in the RNA-induced silencing
complex to exert its regulatory function by binding to target
transcripts (6, 12).
Next-generation sequencing (NGS) is an enabling, highthroughput sequencing technology that is capable of profiling
the expression of various RNA species in a genome-wide scale
with single-nucleotide resolution (41, 53). Compared with
hybridization-based techniques, such as quantitative PCR and
microarray, which are more suitable for profiling known genes,
NGS directly sequences RNA transcripts and thus is able to
facilitate de novo discovery of novel miRNA genes and accurate quantification of miRNA expression (9, 32). Recent studies, particularly those based on NGS, have discovered a pool of
miRNAs, miRNA-like RNAs, and their variants that are more
diverse than we previously anticipated. These diverse miRNAs
include canonical and noncanonical miRNAs (7, 13, 57, 65),
miRNA-like RNAs (4, 22, 96, 97), and miRNA isoforms (58,
62) (Fig. 1). Canonical miRNAs are generated from a biogenesis pathway that requires Drosha and Dicer, as discussed
earlier. Noncanonical miRNAs are produced from alternative
biogenesis pathways where the essential player of the canonical miRNA biogenesis pathway, Drosha, is typically not involved. The first example of noncanonical miRNA is the class
of mirtrons, which arise from short, ⬃60 to 100 nt long,
debranched intron lariats that form stem-loop structures that
serve as substrates for Dicer cleavage, thus bypassing the
Drosha/dgcr8 processing (7, 16, 65, 73). Dicer-dependent but
Dgcr8-independent miRNA-like RNAs can also arise from
1094-8341/14 Copyright ©2014 the American Physiological Society
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MicroRNAs IN NORMAL AND PSORIATIC SKIN
Fig. 1. Biogenesis pathways of canonical and noncanonical microRNAs (miRNAs) and miRNA-like RNAs, with miRNA isoforms (isomiRs) included. A: RNA
polymerase II transcribes primary miRNAs (pri-miRNAs) into long single-stranded primary RNA transcripts in the nucleus, where pri-miRNAs form
double-stranded hairpin structures. Pri-miRNAs are then processed to ⬃60 to 70 nt long precursor miRNAs (pre-miRNAs) by the Microprocessor
(Drosha-DGCR8/Pasha complex). After being exported to the cytoplasm by Exportin-5, pre-miRNAs are further processed to ⬃22 nt miRNA/miRNA* duplexes
with 2-nt 3= overhangs by the Dicer1-TRBP/PACT/Loqs complex. During the process, variants of miRNAs, termed isomiRs, can be produced due to inaccurate
Drosha and/or Dicer processing. Finally, mature miRNAs are loaded into Argonaute (Ago) protein complexes, while miRNA* are discarded. b: mirtron-derived
pathway. Mirtrons are debranched short introns forming pre-miRNA hairpin mimics, thus bypassing the Drosha process. C: snoRNA-derived pathway. A number
of box H/ACA snoRNAs can give rise to Ago-associated, miRNA-like species in a Drosha/DGCR8 independent, Dicer-dependent manner. d: short-hairpin RNAs
(shRNAs) are directly transcribed as short RNAs folding to pre-miRNA-like hairpins, thus bypassing the Drosha process. E: in the case of tRNA-Ile/miR-1983,
a pre-tRNA folds into an alternative structure consisting of a pre-miRNA-like hairpin. F: a number of tRNA and miRNA polycistrons in murine gamma
herpesvirus are processed to pre-miRNA-like hairpins by tRNase Z instead of Drosha. G: miRNAs derived from a terminal hairpin of an endogenous siRNA
(endo-siRNA) precursor. Endo-siRNA precursors are processed by the Dicer2 complex to yield pre-miRNA-like terminal hairpins, which are then processed by
the Dicer1 complex. H: Dicer-independent pathway. Drosha cleavage of pri-miR-451 proceeds normally, and the pre-miR-451 is directly incorporated into Ago2
without Dicer cleavage. I: Dicer-independent and tRNase Z-dependent pathway. A 3=-trailer fragment of a precursor tRNA is released by tRNase Z cleavage.
Organisms that represent each pathway (B–I) are indicated at the bottom of the panels. D.m., Drosophila melanogaster, G. lamblia, Giardia lamblia. Adapted
and modified from Fig. 1 of (57) with permission.
local hairpin formation within larger noncoding RNA (ncRNA)
species, such as small nucleolar RNAs (snoRNAs) (4, 10, 22).
miRNAs are typically defined as the most abundant small
RNAs on pre-miRNA hairpins. Nevertheless, other less abundant but cognate small RNAs from the same pre-miRNAs,
which differ by a few bases from miRNAs, have been reported
(46, 72). These miRNA variants have been named miRNA
isoforms, or isomiRs (59), and observed to exist in animals,
plants, and viruses (21, 23, 68). isomiRs can function as regular
miRNAs (31, 95, 98); they often share common mRNA targets
with their companion miRNAs but may also have their own
exclusive target genes (98). The emergence of such diverse
miRNAs as additional gene expression regulators with potential functions complementary to that of canonical miRNAs
reflects the robustness and plasticity of miRNA-mediated gene
expression regulation.
It has been estimated that miRNAs regulate over one-third of
protein-encoding mRNAs in humans (24, 50). In mammalian
skin development, recent studies have revealed that the interaction between miRNAs and their target mRNAs is critical in
regulating distinct signaling pathways during cell differentiation (48, 104). Noncanonical miRNAs, miRNA-like RNAs,
and isomiRs in normal and psoriatic human skin are also of
interest and have recently been reported (38, 96). Dysregula-
Physiol Genomics • doi:10.1152/physiolgenomics.00157.2013 • www.physiolgenomics.org
Review
MicroRNAs IN NORMAL AND PSORIATIC SKIN
tion of miRNAs and their regulated targets has been implicated
in the pathogenesis of psoriasis (75, 82, 108) as well as other
forms of disorder of the skin, including malignant melanoma
(11, 60, 76, 77). Such knowledge of the aberrantly expressed
small ncRNAs (sncRNAs) in psoriatic skin has suggested
functional roles of sncRNAs in psoriasis. An interesting and
emerging theme from these studies is that miRNAs that take
important parts in early skin development can also function in
critical ways in psoriasis. This theme of “what goes wrong
early in life can go wrong again later in life” echoes a similar
scenario that dysregulation of some miRNAs critically important during early cardiovascular muscle development contributes to cardiovascular diseases (51). This emerging theme on
miRNAs suggests that these miRNAs may potentially be excellent candidates for therapeutic treatment of psoriasis. We
discuss in this short review the latest development in identification and characterization of miRNAs and recent findings
about their regulatory functions during skin development and
in normal and psoriatic skin. We finish by sharing our view on
challenges to be addressed for future development.
miRNAs DURING SKIN DEVELOPMENT
Significant progress has been made in identifying miRNAs
and characterizing their specific functions in skin morphogenesis and homeostasis. Several miRNAs with such functions
have been studied (Table 1). Initial efforts have been devoted
to discovering novel miRNAs (45), investigating phenotypes
of Dicer and Dgcr8 skin conditional knockouts (1, 102), and
determining their spatiotemporal patterns of expression in mammalian skin by using cloning and sequencing methods (102).
By investigating phenotypes of mutants knocking out either
Dicer or Dgcr8 in murine embryonic skin, the importance of
miRNAs in skin development has been revealed (1, 102).
Overall, mutants of Dicer and Dgcr8 conditional knockouts
present similar phenotypes of severe defects in murine embryonic skin development (103). Specifically, both mutants have
been characterized by rough skin, failure to gain weight,
defects in hair follicle down-growth, abnormal apoptosis, and
no more than 6-day survival after birth (103). Hyperproliferation has been observed in the Dicer conditional knockout
epidermis, showing the importance of miRNAs in regulating
epidermal proliferation (1).
Profiling miRNA expression at epidermal skin and hair
follicle at embryonic day 17.5 (E17.5) has revealed a set of
differentially expressed murine miRNAs between the two
places. (102). For example, the highly expressed microRNA
(miR)-199 family is only found in the hair follicle but not from
the epidermis at E17.5, indicating a potential regulatory function that relates to hair morphogenesis (102). Further investi-
115
gation by profiling miRNA expression in murine skin at embryonic day 13.5 (E13.5) and day 15.5 (E15.5) has revealed
that miR-203 is barely detectable in E13.5 skin but emerges as
one of the most abundant miRNAs after E15.5. Phenotypic
difference between E13.5 and E15.5 skin is also prominent.
When only single-layered multipotent embryonic skin stem
cells exist at E13.5, the stratification of epidermis begins after
E15.5, suggesting that miR-203 has a critical function in skin
differentiation and stratification (104).
To appreciate the spatiotemporal pattern of miR-203
expression, in situ hybridization (ISH) has been carried out
to localize the expression of miR-203 in great detail. It has
been shown that the expression of miR-203 depends on the
stages of skin development and is cell specific; it is highly
expressed only in differentiated cells of mature skin such as
suprabasal epidermis and inner root sheath of the hair
follicle, but not in progenitor or stem cells such as basal
epidermis and outer root sheath (48, 104). Furthermore,
analysis of zebrafish skin (94) has demonstrated that the
expression of miR-203 is restricted to the outermost layer of
skin, indicating a conserved function of miR-203 contributing to skin differentiation across species.
To comprehend the physiological mechanism of miR-203
functions in differentiated skin cells, targets of miR-203 have
been examined. Among these targets, the transcription factor
p63, which plays an essential role in maintaining “stemness” in
the skin, has been well examined (78). Highly expressed
miR-203 in suprabasal layer has been shown to repress the
expression of p63, thus reducing the proliferative potential of
terminally differentiating keratinocytes (48, 104).
Besides miR-203, recent studies have also recognized
several other miRNAs involved in skin development and
homeostasis (Table 1 and Fig. 2). For example, repression of
miR-34 transcription by p63 is important to maintain cell
cycle progression in epidermal cells (2). miR-125b has been
shown to be highly expressed in skin stem cells, in contrast
to dramatically lower expression in their early progeny
(106). In an inducible mouse system, miR-125b has been
implicated as a repressor of stem cell differentiation (106).
In addition, miR-205 has been found restricted to basal
progenitor cells and had roles in maintaining the expansion
of skin stem cells by antagonizing negative regulators of
PI(3)K signaling (91). miR-200 family and miR-205 are
both highly expressed in normal skin. These miRNAs have
been shown to target ZEB1 and ZEB2, which are both
transcriptional repressors of E-cadherin (17, 28, 42, 67).
Downregulation of the miR-200 family and miR-205 induces an epithelial-to-mesenchymal transition in conjunction with upregulation of ZEB1 and ZEB2 (28).
Table 1. miRNAs that function in skin development
miRNA
miR-203
miR-34a/c
mir-125b
miR-200/miR-205
Function
induced in suprabasal layer to inhibit cell proliferation by repressing p63; regulate the transition from basal
to suprabasal layer in epidermis
repressed by p63 in epidermal cells to maintain cell cycle progression and expression of cyclin D1 and Cdk4
expressed in skin stem cells to balance self-renewal and early lineage commitment
restricted to basal layer. 1) maintains proliferation of progenitor cells
2) maintains epithelial-mesenchymal transition
miR, miRNA: microRNA.
Physiol Genomics • doi:10.1152/physiolgenomics.00157.2013 • www.physiolgenomics.org
Ref. List No.
48, 104
2
106
91
28, 42, 67
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MicroRNAs IN NORMAL AND PSORIATIC SKIN
Psoriatic Involved Skin
T cell
Normal Skin
Dendritic cell
miR-203
miR-203
miR-135
Suprabasal
p63
Neutrophil
miR-135
LCE1B
IGF1R
miR-205
Basal
ZEB1/2
miR-205
Frk, Inpp4b
Epidermis
Basement Membrane
Dermis
Key
miR-203
miRNAs enriched in suprabasal layer
miRNAs enriched in basal layer
miR-205
miR-142
miRNAs enriched in immune cells
Keratins 5/14
Keratins 1/10
miR-135
miR-155
miR-223
Keratins 6/16/17
Fig. 2. Localization of miRNAs in normal and psoriatic-involved skin. Normal
epidermis contains the basal and suprabasal layers. The basal layer contains
progenitor cells in which marker proteins such as keratin-5 and keratin-14 are
highly expressed, and the suprabasal layer contains mostly differentiated cells
characterized by keratin-1 and keratin-10. miR-203 and miR-135 are highly
expressed in the suprabasal layer and miR-205 is restricted to basal progenitor
cells. In psoriasis lesions, the suprabasal layer is thicker and disorganized,
where keratins 6/16/17 are induced in large amounts in response to trauma.
miR-203 and miR-205 are moderately upregulated (1.6-fold), and miR-135
shows higher upregulation (5-fold) in psoriatic-involved vs. normal epidermis.
With infiltrated immune cells, psoriatic-involved epidermis also contains
miRNAs specific to immune cells such as miR-142 and miR-223.
miRNAs IN PSORIATIC SKIN
Novel miRNAs and miRNA Variations
A recent study has adopted NGS to comprehensively profile
microRNAome in human psoriatic and normal skin (38). Compared with the results from profiling murine skin (102), the
miRNAs that are most abundantly expressed in human and
murine skin largely overlap. Furthermore, the depth of the
collected data has not only allowed detection of low abundant
miRNAs but also enabled discovery of novel human miRNAs
at an unprecedented rate (38). Overall, ⬎200 loci in the human
genome have been identified to host novel miRNAs and
miRNA candidates, and 38 novel miRNAs from this profiling
study have been registered in miRbase (38). Many of these
miRNAs and candidates have been reaffirmed as miRNAs in
other studies. Over one-third of the novel miRNAs are intronic,
and some are of particular interest in skin. The genomic loci of
the intronic miRNAs suggest their coexpression and functional
relationship with their host genes. For example, miR-4632, a
newly identified mirtron, is located within TNFRSF1B, which
has been implicated in psoriatic arthritis (69). Intronic miR6510 is encoded in KRT15, which shows downregulation in
psoriatic skin (30). A known human-specific miRNA, miR944, is located in an intron of p63, a well-characterized
transcription factor with essential function in maintaining
stemness in skin (78).
Several novel miRNAs align uniquely to the antisense
strands of known miRNAs (38). For example, miR-203-AS has
been identified as a distinct miRNA on the DNA strand at the
locus antisense to miR-203 (38). A few known miRNA loci,
such as miR-103, encode similar but distinct miRNAs on both
sense and antisense strands. As a note, distinct function of
antisense miRNA has been described in detail at the miR-iab-4
locus in Drosophila melanogaster, where sense and antisense
miRNAs coordinately regulate Hox genes during larval development (84).
A variety of noncanonical miRNAs and miRNA-like RNAs
have been discovered in human psoriatic and normal skin with
NGS-based profiling (38, 96). The largest group of noncanonical miRNAs discovered is the class of mirtrons; ⬎100 mirtron
candidates have been identified in human skin (38, 96), which
have important implications for biogenesis and function.
Genomic loci of many ncRNAs, such as snoRNAs and tRNAs,
may also host Dicer-dependent but Dgcr8-independent miRNAlike RNAs. For example, miRNA-like RNAs have been identified
from small cajal body-associated RNAs, ACA45, in human (22)
and mouse (4), as well as psoriatic and normal skin (38).
Although there have been several snoRNA-derived miRNAs in
eukaryotes, only one tRNA-derived miRNA has been reported
so far (4). In this case, a murine tRNA, IleTAT, folds into an
alternative secondary structure consisting of a stem-loop hairpin from which mmu-miR-1983 is derived (4). hsa-miR-1983,
a homolog of mmu-miR-1983 located within human tRNAIleTAT, has been detected to express in psoriatic and normal
human skin at a lower level than mmu-miR-1983 in murine
stem cells (96).
A systematic analysis has revealed that miRNA isoforms,
i.e., isomiRs, can consistently originate from a majority of
miRNA hairpins in diverse tissues and across species. Of
particular interest is the class of so-called 5=-isomiRs, whose
5=-ends shift by a few bases from the 5=-ends of the cognate
miRNAs (98). A number of miRNA loci that are essential for skin
development and homeostasis produce substantial amounts of
5=-isomiRs. Particularly, the 5=-isomiR from hsa-miR-203 hairpin
accumulates to the same level of abundance as the major miR203 in human psoriatic and normal skin (Table 2) (98). Murine
mmu-miR-203 hairpin also carries an abundant 5=-isomiR in
murine skin (98), suggesting that the mechanism of generating
5=-isomiRs is conserved in mammals. In addition, miR-142 and
miR-223, two hematopoietic-specific miRNAs, have high 5=heterogeneities in human psoriatic lesions (98). miR-142 is
highly expressed in dendritic cells (86) and miR-223 in neutrophils in humans and mice (5, 47). The abundant expression
of miR-142 and miR-223 can be anticipated, given that immune cells including dendritic cells and neutrophils are known
to infiltrate in affected skin lesions (38, 44).
With a large pool of novel miRNA candidates, experimental
validation further supports endogenous expression of novel
miRNAs in human skin. For example, stem-loop quantitative
real-time PCR (qRT-PCR) has showed that novel miRNAs,
including miR-203-AS, miR-3613, and miR-4490, have visible
bands of the same length of miR-203 in normal skin (38).
Stem-loop qRT-PCR uses primers specific to sequences in the
loop regions of miRNAs so that they have higher RT efficiency
than the conventional qRT-PCR and are able to discriminate
among paralogous miRNAs (15, 43).
Ectopic expression in HEK293 cells has indicated that miR203-AS undergoes miRNA biogenesis processing and incorporates into the Argonaute 2 (AGO2) protein (38). qRT-
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Table 2. miRNAs that express aberrantly in human psoriatic skin and relative amount of their companion 5=-isomiRs
miRNA
miR-31
miR-977
miR-135b/miR-7
miR-1983
miR-21
miR-203-AS
miR-155/miR-142/miR-146a
miR-223
miR-203
miR-205
miR-99a/miR-100
mir-10a
miR-124
miR-4490
Description
regulates cytokine/chemokine expression via targeting serine/threonine kinase 40 (STK40)
mirtron; upregulated in psoriatic skin
targets late cornified envelope-1B (LCE1B); impairs barrier development and response to
environmental stimuli
tRNA-derived human homolog of murine miR-1983
contributes to T cell-derived psoriatic skin inflammation
antisense to miR-203
cell fate decisions in hematopoietic development
suppresses cell proliferation by targeting IGF-1R
regulates the transition from basal to suprabasal layer in epidermis
primarily in the basal layer expressed in normal skin and regulates the transcriptional
repressor of E-cadherin to maintain epithelial-mesenchymal transition
inhibits angiogenesis by repressing the mammalian target of rapamycin (mTOR) in
endothelial cells
regulates the behavior of endothelial cells during angiogenesis
downregulation in skin cancer, cutaneous squamous cells
novel miRNA from intergenic region
Fold Change (PP/NN)
IsomiRs, %
42.9
6.4
5.6/3.1
0.4
1.3
0.4/1.0
4.9
4.0
2.7
2.7/2.5/2.3
2.5
1.6
1.6
0.2
0.6
7
1.1/46/0.8
9.8
43
0.5
⫺2.1/⫺2.3
⫺2.3
⫺5.9
⫺8.1
3.1/0.7
22
23
1.2
Fold change is a value of miRNA expression in psoriatic skin (PP) divided by that in normal skin (NN). IsomiRs, the percentage of reads mapping to miRNA
hairpins identified as 5=-isomiRs.
PCR has also confirmed the expression of miRNA-like
RNAs from noncanonical miRNAs, including miR-6499
(mirtron) and miRNAs from tRNA-pseudo-TTA and
snoRNA-U60, in normal human skin (96). Ectopic expression of these miRNA-like RNAs has shown their enrichment
in AGO2 immunoprecipitates, suggesting that they can
associate with AGO2 protein (96).
Aberrant Expression of miRNAs in Psoriatic Skin
In addition to playing critical roles in skin development,
miRNAs also regulate gene expression in skin disorders, including psoriasis. Earlier studies using microarray-based
miRNA profiling have implicated the involvement of a number
of miRNAs in pathogenesis of psoriasis (83, 108). Profiling
using NGS, which is sensitive to low abundant transcripts, has
identified 125 miRNAs from a diverse origins of canonical and
noncanonical miRNAs as well as 5=-isomiRs that exhibit more
than twofold differential expression in psoriatic skin (Supplemental Table S1) (38, 96, 98).1 The majority of the differentially expressed miRNAs are upregulated (90 upregulated vs.
35 downregulated) in psoriatic-involved (PP) skin vs. normal
(NN) skin. This result is consistent with the overall mRNA
expression changes in psoriatic skin, where there are more
upregulated than downregulated mRNA transcripts and substantially fewer differentially expressed miRNAs between psoriatic-uninvolved (PN) skin vs. NN skin (30, 107).
A subset of differentially expressed (DE) miRNAs has been
validated by stem-loop qRT-PCR, including 12 significantly
DE miRNAs (8 upregulated and 4 downregulated) in PP skin
compared with PN or NN skin (38). The most highly upregulated miRNAs in psoriatic skin include the abundantly expressed miR-21 and miR-31 (4- and 43-fold, respectively;
Table 2), which are potential proangiogenic miRNAs (92).
Upregulation of miR-21 and miR-31 has been observed in
various cancers including skin cancer (74). miR-155, miR-1423p, and miR-146a, which regulate various cell fate decisions in
hematopoietic development (27), show ⬃2.5-fold upregulation
1
The online version of this article contains supplemental material.
in PP vs. NN skin (Table 2). miR-203-AS, discovered in
human skin, has also been validated by qRT-PCR to have a
2.7-fold upregulation in psoriatic skin (38). Interestingly,
miR-203, which plays a critical role in skin development,
shows a moderate 1.6-fold upregulation in psoriatic vs.
normal skin (38).
The most significantly downregulated miRNAs in psoriatic
skin include miR-124 and miR-4490 (5.8- and 8.0-fold downregulated, respectively; Table 2). miR-124 also exhibits downregulation in the cutaneous squamous cell, one of the most
common skin cancers (100). Several highly expressed miRNAs
including miR-10a, miR-99a, and miR-100 (Table 2) in human
skin also exhibit significant downregulation (2- to 2.3-fold) in
psoriatic skin.
Although the overall abundance of noncanonical miRNAs is
low in human skin, 12 of them, including hsa-miR-1983
(Supplemental Table S1), show differential expression in PP
and/or PN skin (96). The differential expression of hsa-miR937 (Table 2), which is recently reclassified as a mirtron, has
also been validated by qRT-PCR (96). Furthermore, 18 5=isomiRs also exhibit aberrant expression in psoriatic skin (98).
One prominent example is the 5=-isomiR from miR-203; the
5=-isomiR is more than twofold upregulated in psoriasis. In
addition, 5=-isomiRs from miR-142 and miR-223 are upregulated by 2.3- and 2.5-fold in psoriatic vs. normal skin. Given
the high abundance and upregulation of many 5=-isomiRs in
psoriasis, DE miRNAs and 5=-isomiRs may be important for
pathogenesis of psoriasis.
Overall, the dramatic alteration in miRNA expression in
psoriatic skin reflects the pathogenic features of psoriasis such
as defects in skin cells, infiltration of immune cells, and
impaired vasculature.
Functions of DE miRNAs in Psoriasis
An early study exploring the function of miRNAs in psoriasis has revealed an upregulation of miR-203 in psoriatic skin;
miR-203 has been implicated in targeting suppressor of cytokine signaling 3 (SOCS3) (83). However, subsequent studies
have challenged the conclusion that SOCS3 is a genuine target
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of miR-203 (48, 104). Furthermore, miR-203 has been characterized as an inhibitor of cell proliferation by targeting the
transcription factor p63 in normal skin (Table 1 and Fig. 2) (48,
104). Thus, it is arguable for miR-203 to be downregulated in
psoriatic skin, potentially accounting for the hyperproliferative
skin involving a proinflammatory response. miR-203, however, has been observed to be slightly upregulated in PP skin in
several studies (38, 83, 108), suggesting a minor effect of
miR-203 to suppress the pathogenic hyperproliferation in psoriatic skin. Although further study is needed to reconcile the
disparity over miR-203 targets and to determine the function of
miR-203 in psoriatic skin, it has been speculated that the newly
identified miR-203-AS as well as its cognate miRNA isoform
(see below) may indicate their role in psoriasis (38, 98).
miR-21 and miR-31 are among the most abundant miRNAs
with dramatic upregulation (4- and 40-fold, respectively; Table
2) in psoriatic lesions (38). The expression of miR-21 in
epidermal cells and dermal T cells between psoriatic and
healthy skin has also been examined, showing an elevated
expression in both cell types (56). Inhibition of miR-21 increases the rate of apoptosis in activated T cells, suggesting
that miR-21 suppresses apoptosis in activated T cells. Therefore, overexpression of miR-21 in psoriatic lesions may reflect
the infiltration of activated T cells in psoriatic skin, contributing to T cell-derived psoriatic skin inflammation (56). Overexpression of miR-31 has been shown to contribute to skin
inflammation in psoriasis lesions by regulating the production
of inflammatory mediators and leukocyte chemotaxis to the
skin (99). Specifically, miR-31 regulates cytokine/chemokine expression via targeting serine/threonine kinase 40
(STK40), a negative regulator of NF-␬B signaling, in keratinocytes (99). Besides, transforming growth factor-␤1, a
cytokine highly expressed in psoriasis epidermis, has been
shown to induce upregulation of miR-31 in keratinocytes in
vitro and in vivo (99).
miR-135b and miR-7, which are upregulated in psoriatic
skin (Table 2), have been reported to regulate late cornified
envelope-1B (LCE1B) through direct interactions with the
3=-untranslated region of LCE1B (39). The LCE gene family is
known to have dozens of members that are clustered within the
epidermal differentiation complex region on human chromosome 1. LCE genes are transcribed synergistically in response
to environmental stimuli such as calcium levels and ultraviolet
light (36). In skin, LCE1B is normally expressed in a skin
barrier but shows a 2.1-fold downregulation in psoriatic skin
(30). Therefore, downregulation of gene LCE1B targeted by
upregulated miR-135b and miR-7 may result in defects in
barrier development, contributing to the pathogenesis of psoriasis.
Downregulated miRNAs are of the same significance as
upregulated miRNAs. miR-10a regulates the behavior of endothelial cells during angiogenesis by positively titrating
proangiogenic signaling in zebrafish and human (33). Downregulation of miR-10a may contribute to abnormal behavior of
endothelial cells in psoriasis. miR-100 is an antiangiomiR that
has been shown to inhibit angiogenesis by repressing the
mammalian target of rapamycin (mTOR) in endothelial cells
(29). miR-99a has the same seed (ACCCGUA) as miR-100 and
thus is anticipated to have a similar target specificity (49).
Indeed, miR-99a and miR-100 have been shown to target
mTOR in human skin (37). Downregulation of miR-99a and
miR-100 has been observed in diverse cancers such as esophageal squamous cell carcinoma and endometrioid endometrial
carcinoma (85, 90). Given the function of miR-99a and miR100 as inhibitors of angiogenesis, downregulation of the two
miRNAs in psoriatic skin may have an implication in pathogenic characteristics of psoriasis, particularly increased angiogenesis.
A system-wide target analysis has revealed that DE miRNAs
show anticorrelated expression with their target mRNAs (38,
96). In particular, 287 DE mRNAs express anticorrelated with
55 DE canonical miRNAs (43 upregulated and 12 downregulated), and 59 DE mRNAs exhibit expression anticorrelated
with nine noncanonical miRNAs (7 upregulated and 2 downregulated). A gene ontology analysis has shown that the anticorrelated targets of canonical DE miRNAs are significantly
enriched in biological processes such as response to cytokine
stimulus, organic substance, and estrogen stimulus. The genes
related to cytokine stimulus are of particular interest because
overexpression of proinflammatory cytokines, including IFNalpha and TNF-alpha, has been implicated in the pathophysiology of psoriasis (44). The gene ontology analysis also shows
that the enriched molecular functions involve transcription
factor activity and cytoskeletal protein binding. These functional terms are consistent with the early results from mRNA
transcriptome analyses in Refs. 30, 87, suggesting that miRNAs may respond to the dysregulated transcriptome of psoriasis.
Target analyses show that more than half of the targets
between miRNAs and their 5=-isomiRs are different, implying
their potentially distinct functions (98). For example, hsa-miR203 and its most abundant 5=-isomiR share about half (53.7%)
of their common targets. The 5=-isomiR of miR-203 may have
additional and complementary functions with miR-203 by
putatively regulating p63 to affect multiple pathways during
skin development. Overall, DE 5=-isomiRs have a total of 148
anticorrelated pairs with 110 distinct target genes (21 upregulated and 89 downregulated) in psoriatic and normal skin (98).
While 5=-isomiRs are highly expressed in diverse tissues
including skin, their impact on mRNA expression remains to
be studied. Recent studies investigating a few examples of
5=-isomiRs (3, 16, 34) have shown that 5=-isomiRs of miR-223
have exclusive targets that are significantly de-repressed after
the miR-223 gene was knocked out in neutrophils, indicating a
direct impact of 5=-isomiRs on target gene expression (16, 98).
Existing experimental evidence from in vitro target cleavage
assays supports the notion that miR-142-5p and its 5=-isomiR
have different target specificities (3). In light of the fact that
5=-isomiRs are functional, the dysregulated 5=-isomiRs, including those from the loci of abundantly expressed hsa-miR-203,
hsa-miR-142, and hsa-miR-223, are of particular interest in
psoriatic skin.
Cell Type-specific miRNA Expression in Psoriatic Skin
RNA ISH has been adopted to localize miRNA expression to
determine cell-specific expression patterns (40, 94). It has
helped reveal the spatial pattern of miR-203 expression in the
suprabasal layer of the epidermis. Adaption of ISH of miRNAs
in psoriatic skin has also revealed that miR-135b, one of the
upregulated miRNAs, is expressed in the suprabasal epidermis
of psoriatic epidermis but is excluded from the basal layer (Fig.
Physiol Genomics • doi:10.1152/physiolgenomics.00157.2013 • www.physiolgenomics.org
Review
MicroRNAs IN NORMAL AND PSORIATIC SKIN
4 of Ref. 38). In contrast, miR-205 is expressed primarily in the
basal layer of psoriatic uninvolved skin, but not in the basal
and suprabasal layers of PP skin (38). Although miR-205 does
not show more than twofold differential expression in psoriasis, its modest upregulation in psoriatic skin coupled with a
previously described function in the establishment of epithelial
cell fate (28) points toward its potential role in psoriasis
pathogenesis. The spatial patterns of miR-135b and miR-205 in
psoriatic skin suggest a role in keratinocyte differentiation. ISH
of DE miRNAs has also helped recognize the epidermal
infiltration of miR-142-3p, a hematopoietic-specific miRNA,
in psoriatic lesions (Fig. 4 of Ref. 38), consistent with the
infiltration of dendritic cells, where miR-142 is highly expressed, in affected skin lesions (38, 44).
OTHER SMALL RNAs IN NORMAL AND PSORIATIC SKIN
Endogenous siRNAs (endo-siRNAs) arise from long dsRNA
transcripts from repetitive or transposable elements (66, 88,
93), whose biogenesis requires Dicer but not Drosha/Dgcr8 (3,
10). Endo-siRNAs have been described in plants (12, 14),
Caenorhabditis elegans (72), D. melanogaster (19, 26, 63, 64),
and murine embryonic stem cells and oocytes (4, 88, 93). It has
also been indicated that endo-siRNAs are expressed in murine
embryonic skin (103). Endo-siRNAs have functions to repress
mobile elements and to regulate downstream targets (88).
In human skin, specific sncRNAs from repeat regions are
endo-siRNA candidates. In particular, an siRNA candidate
derived from an Alu-short interspersed element exhibits a
17-fold upregulation in PP skin (96). This endo-siRNA resides
within an intron of the gon-4-like (GON4L) gene on chromosome 1, where three Alu-SINEs appear in tandem. In sharp
contrast to the huge upregulation of the endo-siRNA, the
expression of the host gene GON4L shows little variation
between PP and NN skin. This discrepancy implies that the
endo-siRNA and the host gene may be transcribed or processed
independently. The cluster of the siRNAs appears only in the
first two Alu SINEs, suggesting that the repetitive elements
may harbor the novel endo-siRNAs instead of the intron. A few
targets, such as MDM4 (mouse double minute 4 homolog), are
anticorrelated with the Alu-derived endo-siRNAs (96). This
gene is an inhibitor of p53 that is frequently upregulated in
cancers (20, 89) but modestly downregulated in psoriasis (61).
Thus, the downregulation of MDM4 in psoriasis, which may be
mediated by the novel Alu-SINE-derived siRNA, might be one
factor that distinguishes the benign hyperplasia in PP skin from
cancerous tumors. MDM4 is also a putative target of canonical
miRNA miR-19b that is upregulated by 2.1-fold in psoriasis.
These results indicate MDM4 is tightly regulated by miRNAs
and endo-siRNAs in psoriatic skin.
SUMMARY AND FUTURE DIRECTIONS
Although still in its infancy, the study of miRNAs and endosiRNAs in mammalian skin and skin disorders has already provided deep insights into this novel layer of gene regulation.
Knowledge about the aberrantly expressed sncRNAs in psoriatic
skin has laid a foundation for understanding the roles of miRNAs and endo-siRNAs in psoriasis. We now have a good
collection of miRNAs as well as their validated and putative
targets, many of which are discussed here, that provide not
119
only new knowledge of psoriasis mechanisms, but also novel
threads for future research.
An interesting and converging theme has emerged from the
results and findings obtained so far, i.e., two key miRNAs,
miR-203 and miR-205 (Tables 1 and 2 and Fig. 2), which play
essential roles in early skin development also function in
critical ways in psoriasis. This theme of “what goes wrong
early in life can go wrong again later in life” echoes a similar
observation that miR-1 and miR-133 are critically important
during early cardiovascular muscle development as well as in
cardiovascular diseases (51). This emerging theme on miRNAs
suggests that these miRNAs may potentially be excellent
candidates for therapeutic treatment of psoriasis.
Despite significant progress that has been made so far, recent
results and findings require more research to be done to unravel
the complex genetic networks involved in the etiology of
autoimmune skin disorders such as psoriasis. First, it is important, albeit challenging, to build a high-quality regulatory
network underlying psoriasis. Such a network can be used to
identify the major genetic components of the disease. Building
such a network, nevertheless, requires a comprehensive profile
of the total transcriptome, including mRNA genes, miRNAs,
and other sncRNA species. A good collection of such transcriptome data can also be used to address the second challenge, i.e., identification and characterization of potential long
noncoding RNAs (lncRNAs) in psoriasis. Although little results on lncRNA have been reported yet for psoriasis, it is
possible to hypothesize the involvement of novel genetic elements, particularly lncRNAs, since extensive research has not
brought us close to the genetic culprits of the disease. The third
challenge is to integrate the information of genotypic variations, e.g., single nucleotide polymorphisms and copy number
variations, with the data of transcriptome variations in hunting
for causal genetic variations that ultimately lead to disease
phenotypes. The results from biological assays analyzing individual genes and genome-wide profiling have shown that both
techniques are effective and complementary to each other. It
will be more effective, although challenging, to integrate the
results from genome-wide profiling with experimental functional analyses of key elements. For example, the current
results have pointed to a few miRNAs, e.g., miR-203, miR205, and miR-125, to be critical players in skin development
and psoriasis. Their regulatory functions need to be further
scrutinized in animal models or cell lines with, e.g., lossand/or gain-of-function mutants of these miRNAs. The recent
progress on transgenic technologies, such as the latest TALEN
(105) and CRISPR/Cas (18, 52, 101) techniques, can be adopted to meet the challenge of such functional analysis. They
can be used to manipulate individual genes for their functions
in psoriasis and also to develop animal models for psoriasis
research.
Finally, we are optimistic with the prospects of this field.
Because of the easy accessibility of the skin and the collective
effort of the research community, we anticipate that skinrelated diseases will be among the first to be treated with small
RNA-based therapies.
ACKNOWLEDGMENTS
Thanks to Kevin Zhang for a critical reading of the manuscript.
Physiol Genomics • doi:10.1152/physiolgenomics.00157.2013 • www.physiolgenomics.org
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MicroRNAs IN NORMAL AND PSORIATIC SKIN
GRANTS
The research was supported by National Institutes of Health Grants
R01GM-100364 and RC1AR-058681, National Science Foundation Grant
DBI-0743797, and an internal grant of Jianghan University, Wuhan, Hubei,
China.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: J.X. performed experiments; J.X. and W.Z. analyzed
data; J.X. and W.Z. interpreted results of experiments; J.X. prepared figures;
J.X. and W.Z. drafted manuscript; J.X. and W.Z. edited and revised manuscript; W.Z. conception and design of research; W.Z. approved final version of
manuscript.
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