application of epigenetics in dermatological research and skin management.pdf

1. J Cosmet Dermatol. 2021;00:1–11. wileyonlinelibrary.com/journal/jocd | 1
© 2021 Wiley Periodicals LLC
1 | GENETICS AND EPIGENETICS
The deciphering of the double-­
helix structure of DNA is a landmark
discovery in the field of life sciences. Classical genetics believes that
nucleic acid is the molecular basis of heredity, and the genetic infor-
mation of life is stored in the base sequence of nucleic acid. Because
of these discoveries, a central dogma became popular in the field of
life sciences, which equated life with DNA→RNA→Protein.1
There is
no doubt that it is accurate, but it is a simplified statement. There are
many phenomena in real life that cannot be explained by the central
dogma, and epigenetics came into being. Epigenetics is defined as the
study of heritable changes in the phenotype that occur without po-
tential changes in the genome sequence.2
Epigenetics is the natural
development of genetics and is established on the basis of genetics.3
The term epigenetics was first proposed by embryologist
Conrad Waddington in 1942. He defined epigenetics as the branch
of biology that studies the causal interaction between genes
and their products, and this interaction leads to the phenotype.4
Epigenetics is mainly to study the connection between genotype
and phenotype and the complex developmental processes that exist
between them.5
Broadly speaking, epigenetics is the bridge be-
tween genotype and phenotype. It refers to the phenomenon that
gene expression can be heritable when the DNA sequence does not
change.6
Today's epigenetic research mostly focuses on the study of
covalent and non-­
covalent modifications of DNA and histones, as
well as the study of some non-­
coding RNA modifications.7
Different
from diseases caused by DNA sequence changes, since many epi-
genetic mutations are reversible processes, diseases caused by
Received: 23 March 2021 | Revised: 25 June 2021 | Accepted: 19 July 2021
DOI: 10.1111/jocd.14355
R E V I E W A R T I C L E S
Application of epigenetics in dermatological research
and skin management
Jianbiao He BS1,2
| Huaming He PhD1,2
| Yufeng Qi BMS3
|
Jie Yang MCS3
| Leilei Zhi MS3
| Yan Jia PhD1,2
1
Beijing Key Laboratory of Plant
Resources Research and Development,
College of Chemistry and Materials
Engineering, Beijing Technology and
Business University, Beijing, China
2
College of Chemistry and Materials
Engineering, Key Laboratory of Cosmetic
of China National Light Industry, Beijing
Technology and Business University,
Beijing, China
3
Shandong Huawutang Biological
Technology Co, Ltd, Shandong, China
Correspondence
Yan Jia, Beijing Key Laboratory of Plant
Resources Research and Development,
Key Laboratory of Cosmetic of China
National Light Industry, College of
Chemistry and Materials Engineering,
Beijing Technology and Business
University, Beijing 100048, China.
Email: jiayan@btbu.edu.cn
Funding information
This work was supported by the fund
for Excellent Young Scholars of Beijing
Technology and Business University
(19008021151)
Abstract
Background: Epigenetics has recently evolved from a collection of diverse phenom-
ena to a defined and far-­
reaching field of study. Epigenetic modifications of the ge-
nome, such as DNA methylation and histone modifications, have been reported to
play a role in some skin diseases or cancer.
Aims: The purpose of this article was to review the development of epigenetic in re-
cent decades and their applications in dermatological research.
Methods: An extensive literature search was conducted on epigenetic modifications
since the first research on epigenetic.
Results: This article summarizes the concept and development of epigenetics, as well
as the process and principle of epigenetic modifications such as DNA methylation,
histone modification, and non-­
coding RNA. Their application in some skin diseases
and cosmetic research and development is also summarized.
Conclusions: This information will help to understand the mechanisms of epigenet-
ics and some non-­
coding RNA, the discovery of the related drugs, and provide new
insights for skin health management and cosmetic research and development.
K E Y W O R D S
dermatological research, DNA methylation, epigenetics, histone modification, non-­
coding RNA

2. 2 | HE et al.
epigenetic abnormalities are relatively easy to treat. This is one of
the reasons why epigenetics has become a hot spot in the field of
biomedical research.8,9
Here, we aim to briefly introduce several epi-
genetic modifications, discuss the role of epigenetic modifications
in gene regulation, and summarize the application of epigenetics in
skin research.
2 | EPIGENETIC MODIFICATIONS
Epigenetic modifications involving gene regulation such as DNA
methylation, histone modification, and non-­
coding RNA regulation
are introduced below.
2.1 | DNA methylation
DNA methylation is an important form of epigenetics, which plays
an important role in mammalian development, differentiation,
and maintenance of cell identity by controlling gene expression.10
DNA methylation is currently the most clearly studied and most
important form of epigenetic modification. The specific process of
DNA methylation is as follows: DNA methyltransferases (DNMTs)
use S-­
adenosylmethionine as a methyl donor to transfer the me-
thyl group to the fifth carbon atom of cytosine in the DNA double
strand and form 5-­
methylcytosine. The DNMTs that catalyze this
reaction mainly include DNMT1, DNMT3A, and DNMT3B, which
have a nitrogen-­
terminal regulatory domain and a carbon-­
terminal
catalytic domain.11
Among them, DNMT1 is the first mammalian
DNMT cloned and has a strong preference for hemimethylated
DNA and maintains the original methylation pattern during replica-
tion.12,13
In contrast, DNMT3A and DNMT3B are called de novo
methyltransferases, which are mainly responsible for establishing
DNA methylation patterns during embryogenesis and catalyzing
the formation of new methyl sites using unmethylated DNA as a
template.14
These two proteins have different functions during the
entire embryonic development process, showing differences in
space and time.
DNA methylation in mammalian cells mainly occurs in cytosine
at CpG sites. The CpG sequence is unevenly distributed in the mam-
malian genome. It exists in two forms: One is scattered in the DNA
sequence; the other is in a highly aggregated state, called CpG is-
lands. CpG islands are mainly located in the promoter and first exon
regions of genes. About 60% of the promoters of genes contain CpG
islands. CpG island methylation is essential for gene suppression and
expression.15
However, mammalian genomes show particularly high
levels of CpG methylation, with 70%–­
80% of CpG being methylated,
despite some tissue-­
specific differences.16
DNA methylation has many important physiological sig-
nificances in organisms.17
Normal methylation is necessary to
maintain cell growth and metabolism. Specific manifestations in-
clude maintenance of chromatin structure, genetic imprinting, X
chromosome inactivation, cell differentiation, and embryonic de-
velopment. Abnormal DNA methylation may cause various dis-
eases, such as cancer, aging, and skin diseases.18-­20
In addition, the
ten-­
eleven translocation protein was found to mediate the elim-
ination of DNA methylation, indicating that DNA methylation is
a reversible process.21
DNA demethylation can protect gene re-
gions of the genome from the powerful methylation-­
based trans-
poson defense system and activate the expression alleles of some
imprinted genes.22
Obviously, studying DNA methylation is very
helpful for understanding biological growth, development, and dis-
ease treatment.
2.2 | Histone modification
Histone modifications are another important way of epigenetic
modification, with special physiological and biochemical functions.
Until the early 1990s, histones were generally considered as packag-
ing materials for DNA and had no role in gene regulation.23
With the
deepening of research, scientists discovered that histones play an
important role not only in the regulation of gene expression, but also
in DNA damage repair, DNA replication and recombination, and the
regulation of chromatin state.24,25
In the growth state of cells, DNA
exists in the nucleus as the chromatin form. Nucleosome, the basic
structural unit of chromatin, is composed of DNA and histones. In
the nucleosome, it consists of an octamer of four core histones (H3,
H4, H2A, and H2B), surrounded by 147 base pairs of DNA. The core
histones are mainly globular. A distinguishing feature of histones,
especially their tails, is that they have a large number of modified
residues.25
The free N-­
terminal and globular core region of his-
tone peptides can be subjected to various modifications, including
acetylation, methylation, phosphorylation, ubiquitination, and small
ubiquitin-­
like modifier (SUMO).26
Histones undergo post-­
translationally modifications (PTMs).
These PTMs are deposited and removed by specialized histone-­
modifying enzymes,27
such as histone methyltransferase, histone
acetyltransferase, and histone kinase. Because of this feature,
epigenetic modification is reversible, so it can dynamically ad-
just chromatin structure to activate or silence gene expression.28
General histone modification requires one or more different
modifications to have synergistic or antagonistic effects. These
diverse modifications can generate a large number of specific sig-
nals to form a histone code, which can be read by the corre-
sponding protein, and then regulate the expression of genes to
produce different downstream events.29
Histone modification
is an important epigenetic marker. Abnormal histone modifica-
tion enzyme activity and abnormal histone modification level are
closely related to a variety of human diseases including cancer,
making it a very promising and attractive disease biomarker.30
Therefore, strengthening the research and understanding of his-
tone modification is essential for disease diagnosis and the devel-
opment of related drugs.

3. | 3
HE et al.
2.3 | Non-­
coding RNA modification
Non-­
coding RNAs (ncRNAs) is a type of heterogeneous RNA that is
not translated into protein. Although some of these RNA products
may not have specific functions, some ncRNAs play a role in regulat-
ing gene expression and regulating cellular processes.31,32
NcRNA
can be divided into basic non-­
coding RNA and regulatory non-­
coding
RNA. Basic non-­
coding RNA can be divided into ribosomal RNA,
transfer RNA, small RNA, and small nuclear RNA. Regulatory non-­
coding RNA can be divided into microRNA (miRNA), Piwi-­
interacting
RNA (piRNA), small interfering RNA (siRNA), and long non-­
coding
RNA (lncRNA).33
NcRNA is widely involved in various important
links in life activities, such as the development and differentiation
of individual organisms, reproduction, cell apoptosis, and cell repro-
gramming, and is closely related to human diseases.34-­36
Long non-­
coding RNA (lncRNA) usually refers to non-­
coding
RNA transcripts greater than 200 nucleotides in length. The length
of lncRNAs allows them to fold into a variety of complex structures,
thereby performing diverse and complex regulatory functions in sev-
eral biological processes.37
LncRNA has a broad tissue expression
profile. Compared with mRNA encoding proteins, their expression
abundance is generally relatively low, but they have stronger tissue
and cell expression specificity. LncRNAs can regulate gene expres-
sion in cells and organisms through a variety of different ways.38
In
addition, lncRNA can also interact with other types of RNA in cells,
and thus regulate their stability, splicing, translation, and metabolism
to modulate gene expression. Since lncRNA is an important regu-
lator of cell gene expression, the incorrect regulation of lncRNA in
the cell will lead to abnormal cell function and cause various human
diseases.
In addition to lncRNA, there are more and more studies on
miRNA. MiRNA is a type of small non-­
coding RNA with a length of
18–­
25 nucleotides. As a post-­
transcriptional regulator, it plays a very
important role in the regulation of gene expression in eukaryotes.
When miRNA binds to its target mRNAs in a completely comple-
mentary manner after transcription, it will cause the degradation of
the target mRNAs or inhibit its translation, and finally achieve the
purpose of inhibiting the expression of specific genes.39
miRNA
itself can target genes that control epigenetic pathways. A com-
plex feedback network is formed between miRNAs and epigenetic
pathways—­
miRNA regulatory loops, which organize the entire gene
expression profile.40
With the deepening of research, more and more
evidence reveals the important role of miRNAs in cancer. Therefore,
characterizing the epigenetic regulation of miRNA will provide new
opportunities for the development of cancer biomarkers and/or the
identification of new therapeutic targets.41
3 | APPLICATION OF EPIGENETICS IN
LIFE SCIENCES
Epigenetics is currently one of the most active research fields
in biology. It involves the study of a variety of biological
phenomena, such as cell differentiation and development, me-
tabolism, cancer, phenotypic variation, heredity, evolution,
behavior, and even culture.42
It also has a wide range of applica-
tions in the field of life sciences, including botany, cancer, and
some metabolic diseases.
3.1 | Cancer
The activation of oncogenes or the inactivation of tumor sup-
pressor genes has long been considered as the basic mechanism
of carcinogenesis. Past studies on epigenetics have found that
there is an inseparable relationship between epigenetics and
cancer. Various biochemical pathways critical to tumorigenesis
are regulated by epigenetic phenomena, such as nucleosome re-
modeling caused by histone modification, DNA methylation, and
miRNA-­
mediated gene targeting.43
At the same time, epigenetics
can also be used as a method of cancer diagnosis and detection.
For example, DNA hypermethylation, especially hypermethylation
on CpG islands, has been identified as an epigenetic abnormal-
ity observed in several malignant tumors, such as bladder cancer,
colon cancer, and breast cancer. Therefore, analyzing hypermeth-
ylated CpG islands is a promising method for cancer detection and
classification.44
The use of epigenetics can help to diagnose and
detect cancer at a relatively early stage, which can greatly reduce
mortality. At the same time, advanced technologies for detecting
epigenetic changes in the whole genome provide convenience and
promise to promote our ability to develop biomarkers for the early
diagnosis of tumors.
3.2 | Drug development
Since epigenetics is widely involved in a variety of diseases, and
most of the epigenetic modifications is a reversible process, epi-
genetics has received great attention in the development of new
therapeutic drugs. Currently, only two types of epigenetic drugs
have been approved by the US Food and Drug Administration-­
DNA
methylation inhibitors (iDNMTs) and histone deacetylase inhibitors
(HDACIS). Many studies have found that changes in DNA methyla-
tion (such as hypomethylation and hypermethylation) are related
to cancer, genetic diseases, neurological diseases, and autoim-
mune diseases. Since DNA methylation is controlled by DNMTs,
DNMTs have received extensive attention and research as drug
targets. Inhibiting the activity of DNMTs can affect the degree of
DNA methylation in organisms, thereby achieving the purpose of
treating diseases.45
In addition, the emergence of nanotechnology
in medicine, especially the development of nanosystems for epige-
netic drug delivery and targeted release, will help advance person-
alized targeted therapy.46
With the help of nanotechnology, drugs
can be packaged so that they can reach the site of action more
efficiently and accurately, thus shortening the period of disease
treatment.

4. 4 | HE et al.
4 | APPLICATION OF EPIGENETICS IN
SKIN RESEARCH
4.1 | Skin cancer
Skin cancer is one of the most common cancers in the human body,
affecting tens of millions of people worldwide. Over the past four
decades, the prevalence and risk of skin cancer have been increas-
ing. Human skin cancer can generally be divided into malignant mela-
noma and non-­
melanoma skin cancer (NMSC). NMSC includes basal
cell carcinoma (BCC) and squamous cell carcinoma. Among them,
NMSC is more common and has a high incidence worldwide, but it
is highly curable, especially if diagnosed at an early stage. Malignant
melanoma arises from the malignant transformation of melanocytes
and is the most serious and unpredictable skin disease.47
As the most
common skin cancer, BCC is a low-­
grade malignant tumor derived
from basal cells or skin appendages. Its incidence has been increasing
and displays a tendency of younger populations. Excessive exposure
to ultraviolet radiation from the sun is the main cause of the BCC.48
BCC is an epithelial tumor, and metastasis is very rare. However, it
is locally invasive and if left untreated, BCC will infiltrate severely.
T-­
cadherin is a very unique cadherin molecule. A large number of
studies have shown that the occurrence of various cancers is related
to changes in T-­
cadherin expression,49-­51
such as stomach cancer,
colorectal cancer, and prostate cancer. Furthermore, T-­
cadherin
seems to act as a tumor suppressor in these cancers. At the same
time, the decreased expression of T-­
cadherin is related to the patho-
genesis and aggressiveness of BCC, and the abnormal methylation
of its promoter region may be the reason for the low protein expres-
sion. Takeuchi et al.52
studied the expression of T-­
cadherin in archi-
val pathological tissue sections composed of normal counterparts of
skin and various types of BCC to elucidate the relationship between
the invasiveness of BCC and T-­
cadherin. The results of immunohis-
tochemical staining showed that among 51 BBC specimens, 38 cases
(75%) displayed no obvious T-­
cadherin expression. Besides, among
30 specimens of nodular BCC, there were 25 cases (83%) showing
no obvious T-­
cadherin expression. At the same time, their study re-
vealed that allelic loss and promoter hypermethylation play a role in
suppressing T-­
cadherin expression in BCC. In addition, studies have
shown that hypermethylation of tumor-­
related genes, especially the
CDH1 promoter region, often appears in cutaneous squamous cell
carcinomas.53
Abnormal DNA methylation is the characteristic and
cause of many skin cancers. Hence, epigenetics may help to prevent
and treat cancer.
Due to the reversibility of the epigenetic modification process,
the application of epigenetics in skin cancer prevention and cure
treatment has also received extensive attention. Many studies have
shown that the anti-­
cancer components of diet or drugs can change
theepigeneticprocesstoachievethepurposeofpreventionandtreat-
ment,54,55
such as sulforaphane and (-­
)-­
epigallocatechin-­
3-­
gallate
(EGCG). EGCG is the main component of green tea polyphenols,
which have anti-­
inflammatory, anti-­
viral, and anti-­
tumor effects.56
Nandakumar et al. used a well-­
known human epidermoid cancer cell
line A431 as an in vitro model, treated it with epigallocatechin gal-
late, and determined the level of DNA methylation in the cell.55
The
results showed that EGCG treatment decreased DNA methylation
levels in A431 cancer cells, but the process seemed to be relatively
slow. The study also determined that the best effective time period
of EGCG for inhibition of DNA methylation was 6 days. Additionally,
EGCG can also restore or reactivate the expression of the silenced
tumor suppressor genes, p16INK4a
and Cip1/p21 by enhancing his-
tone acetylation in skin cancer cells. Epigenetic regulation of EGCG
on tumor suppressor genes may contribute to the prevention and
treatment of skin cancer and have important implications for clinical
applications.
4.2 | Atopic dermatitis
Atopic dermatitis (AD) is the most common chronic, recurrent, and
inflammatory skin disease, which affects 15%–­
20% of children and
5%–­
10% of adults worldwide.57
Its pathological characteristics are
repeated dry skin desquamation, eczema-­
like lesions, and severe
pruritus. The pathogenesis of AD is complex, but it is generally con-
sidered to be the result of genetic and environmental factors. As we
all know, most AD-­
related genes do not follow Mendel's law, but are
highly heritable. Therefore, patients with familial atopic dermatitis
are more likely to develop AD.58
Although heredity plays an impor-
tant role in disease transmission, the environment plays an impor-
tant role in disease initiation. Statistics showed that the incidence
rate of atopic dermatitis in developed countries, such as Britain and
the United States, was high, while the incidence rate of specific der-
matitis in Africa and East Asia was low. This emphasized the role
of environmental factors in the pathogenicity of atopic dermatitis.59
In addition, seasons, diet, living habits, etc., are all related to atopic
dermatitis, and the mechanism of these findings may be mediated by
epigenetic pathways.
Approximately 70% of patients with AD exhibit elevated
serum IgE levels with allergic reactions and are classified as ex-
ogenous atopic dermatitis.60
Nakamura et al.61
used a real-­
time
quantitative-­
polymerase chain reaction method to detect the
mRNA level of DNMT1 in peripheral blood mononuclear cells
(PBMCs) of patients with atopic dermatitis. The results showed
that compared with the normal control group, atopic dermati-
tis patients with higher serum IgE levels had significantly lower
DNMT1 mRNA levels. This finding suggests that DNMT1 inhibi-
tion and subsequent hypomethylation may play an important role
in the pathogenesis of atopic dermatitis patients with high serum
IgE. Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-­
7-­
like inflammatory cytokine with four α-­
helix bundles. The expres-
sion of TSLP in the skin lesions of AD patients is higher than that in
non-­lesion areas and healthy skin62
and is related to the severity of
the disease and the degree of damage to the epidermal barrier. In
order to investigate whether TSLP overexpression in patients with
atopic dermatitis is regulated by abnormal methylation of the TSLP
promoter in keratinocytes, Luo et al.63
compared the damaged

5. | 5
HE et al.
skin of 10 atopic dermatitis children with the skin of 10 healthy
controls. The results showed that hypomethylation of TSLP pro-
moter and increased expression of TSLP mRNA and protein were
observed in the diseased skin of patients with atopic dermatitis.
It indicates that the DNA demethylation of the TSLP gene pro-
moter may lead to the overexpression of TSLP in the skin lesions
of patients with atopic dermatitis. To date, the most extensive
study on methylation in atopic dermatitis came from Rodriguez
et al.64
who analyzed DNA methylation profiles of whole blood, T
cells, B cells, and skin from 28 patients with atopic dermatitis and
29 healthy controls. The results showed that there was no signifi-
cant difference in DNA methylation in whole blood, T cells, and B
cells between atopic dermatitis patients and controls. However, a
significant difference in CpG methylation was observed between
the damaged epidermis of atopic dermatitis patients and healthy
controls. It suggested that skin rather than blood might be the key
tissue affected by epigenetic disorder in AD.
More and more evidence shows that in addition to DNA methyl-
ation, miRNA-­
mediated gene expression control is also an important
regulatory mechanism of AD. In order to explore the role of miRNAs
in the pathogenesis of atopic dermatitis, Sonkoly et al.65
compared
the global miRNA expression in lesion skin and healthy skin of pa-
tients with atopic dermatitis. The results showed that miR-­
155 was
one of the miRNAs with the highest level of upregulation in patients
with atopic dermatitis. Cytotoxic T lymphocyte-­
associated antigen-­
4
(CTLA-­
4), an important negative regulator of T-­
cell activation in the
skin, is the direct target of miR-­
155. The miR-­
155 was significantly
overexpressed in the skin of patients with atopic dermatitis and may
down-­
regulate the activity of CTLA-­
4, and this inhibition increased
the proliferation of T cells and led to chronic skin inflammation.
Another study showed that long-­
term exposure to tobacco smoke
during pregnancy can cause high expression of miR-­
223 in maternal
and umbilical cord blood, which is related to the low number of Treg
cells. In addition, children with low number of Treg cells at birth have
a higher risk of atopic dermatitis in the first three years of life,66
indi-
cating that the expression level of miRNA-­
223 has an impact on the
risk of subsequent allergy.
4.3 | Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a typical systemic autoim-
mune disease with multiple organs as the target. The main pathologi-
cal feature is the dysfunction of the immune system, the production
of a variety of autoantibodies, and the formation of immune com-
plexes deposited in multiple tissues and organs, causing pathological
damage to the body. The exact pathogenesis of SLE is still unclear,
but it is believed that SLE is also determined by genetic and envi-
ronmental factors. However, only 20% to 30% of identical twins
with identical genetic information have the same incidence of lupus
erythematosus, which indicates that environmental factors and epi-
genetic disorders play a major role in the pathogenesis of this au-
toimmune disease.67
In the past decade, the impact of epigenetic
modifications on innate and acquired immunity has been extensively
and intensively studied, especially in autoimmune diseases.
DNA hypomethylation of T lymphocytes is closely related to
SLE. Studies have found that the methylation level of CD4+ T cells
in patients with SLE is significantly lower than that in normal people.
The decrease in global methylation of CD4 + T cells in SLE patients
is negatively correlated with the increased expression of immune-­
related genes, including CD11a (ITGAL), perforin (PRF1), CD70
(TNFSF7), and CD40LG (TNFSF5), which play an important role in
the pathogenesis of SLE.68-­70
CD11a is a subunit of lymphocyte function-­
associated antigen-­
1
(LFA-­
1). Hypomethylation of itagal gene promoter and its flanking
region in CD4+ T cells of patients with lupus erythematosus results
in increased expression of CD11a, which contributes to the autoim-
mune T-­
cell response.71
The expression of CD11a was also increased
due to hypomethylation of the ITGAL region in normal T cells treated
with DNA methylation inhibitors. CD70 is a member of the TNF-­
α
superfamily and inhibits activated T cells, B cells, and mature den-
dritic cells. It is encoded by the TNFSF7 gene of the B-­
cell costimula-
tory molecule and is overexpressed in lupus CD4+ T cells and normal
CD4+ T cells exposed to DNA methylation inhibitors.72
CD40L is a
type II transmembrane protein encoded by CD40LG on the X chro-
mosome. The CD40LG sequence is also demethylated, and CD40LG
is overexpressed in the CD4+ T cells of women with lupus.73
This
finding helps to explain the high incidence of SLE in women.
The study of histone modification patterns in lupus is not as much
as DNA methylation, but there is a close relationship between abnor-
mal histone hypoacetylation and SLE. Human studies have shown an
overall hypoacetylation of histones H3 and H4 in CD4+ T cells in
patients with SLE, as well as a negative correlation between the level
of H3 histone acetylation and disease activity.74
Histone acetylation
and methylation can be removed by histone deacetylases (HDACs)
and histone demethylases. Trichostatin A (TSA), suberoylanilide hy-
droxamic acid (SAHA), and 4-­
phenyl butyric acid are commonly used
as HDAC inhibitors (HDACi), which can increase the level of histone
acetylation. Treatment of MRL/lpr mice with TSA or SAHA can re-
store the level of histone acetylation in the mice and promote the
significant improvement of the symptoms of lupus erythematosus in
these mice.75
Protein phosphatase 2A (PP2A) is a highly conserved
and ubiquitous serine/threonine phosphatase in eukaryotes. PP2A
is widely involved in the occurrence of allergic diseases, systemic
lupus erythematosus, and other immune disorders. In systemic lupus
erythematosus CD4+ T cells, the overexpression of PP2A can in-
duce the overexpression of IL-­
17a by enhancing the acetylation of
histone 3, thus promoting the production of inflammation in vivo
and the occurrence of lupus erythematosus.76
In addition, overex-
pression of PP2A can lead to a decrease in the phosphorylation of
MEK/ERK, a decrease in DNMT1 expression, and then a reduction in
the demethylation of CD70 promoter and overexpression of CD70.77
In-­
depth study of the epigenetic molecular mechanism of SLE is of
great significance to fully reveal the pathogenesis of lupus erythe-
matosus and brings hope for finding new epigenetic molecular mark-
ers for clinical early diagnosis, prognosis, and efficacy evaluation, as

6. 6 | HE et al.
well as for development of new therapeutic targets and intervention
methods.
4.4 | Psoriasis
Psoriasis is a common chronic recurrent inflammatory skin disease,
accompanied by excessive proliferation of keratinocytes, abnormal
differentiation, and vascular proliferation. Plaque psoriasis is the
most common type of psoriasis. The pathogenesis of psoriasis is
complex, and it is considered to be an organ-­
specific autoimmune
disease triggered by an active cellular immune system. The key
roles of T cells, dendritic cells, and inflammatory cytokines in the
pathogenesis of psoriasis have been identified.78
The pathological
process of psoriasis is very complex, involving a variety of genes in
the immune system and skin, which is the result of genetic and en-
vironmental interaction. However, only 67% of identical twins had
the same genetic information.79
In view of these findings, epigenetic
factors are thought to play a role in the pathogenesis of psoriasis.
It is reported that the factors affecting the course of psoriasis in-
clude infection, stress or mental stress, smoking, drinking, surgery,
and some drug effects. Epigenetics shows a certain degree of plas-
ticity, reversibility, and environmental responsiveness, enabling
them to act as the interface between genes and the environment.80
Identifying epigenetic abnormalities correlated to the occurrence
and development of psoriasis is closely related to the development
of new treatment methods and drug development, because unlike
genetic mutations, epigenetic abnormalities are potentially revers-
ible when using drugs.81
Secreted frizzled-­
related protein (SFRP) 4 is a negative regu-
lator of the Wnt signaling pathway. It can bind to Wnt ligands to
prevent it from binding to frizzled receptors, thereby inhibiting Wnt
signaling activity.82
SFRP4 can directly inhibit the excessive prolif-
eration of keratinocytes induced by proinflammatory cytokines in
vitro. Abnormal promoter methylation leads to the epigenetic down-­
regulation of SFRP4 in inflammatory skin of patients with psoriasis
and il-­
23–­
induced mouse model, which may be closely related to the
excessive proliferation and pathogenesis of keratinocytes in patients
with psoriasis. In addition, intradermal injection of SFRP4 can reduce
the severity of psoriasis-­
like skin phenotypes in the body, includ-
ing reduction in skin desquamation and reduction in leukocyte in-
filtration,83
which also indicates that the down-­
regulation of SFRP4
caused by promoter methylation is closely related to psoriasis.
Another example of abnormal DNA methylation in psoriasis involves
SHP-­
1, which plays an important role in regulating cell growth and
proliferation and has two promoters. Ruchusatsawat et al.84
found
that compared with normal skin, SHP-­
1 promoter region 2 was sig-
nificantly demethylated in keratinocytes of psoriatic lesions, which
led to the upregulation of SHP-­
1 isoform II gene and the loss of con-
trol of keratinocyte growth and differentiation in psoriatic lesions.
In addition to DNA methylation, histone modification is another
important epigenetic mechanism in the pathogenesis of psoriasis.
Zhang et al.85
studied the acetylation degree of global histone H3/
H4 in PBMCs of 30 patients with psoriasis and 20 healthy controls.
The results showed that compared with the normal control group,
the overall histone H4 in PBMCs of patients with psoriasis vulgaris
showed a low acetylation state. The degree of histone H4 acetyla-
tion was negatively correlated with disease activity, which suggested
that histone modification might be related to the pathogenesis of
psoriasis. The expression of HDAC1 and keratinocyte proliferation
markers, such as p63 and PCNA, increased significantly in patients
with psoriasis, which may contribute to the formation of clinical phe-
notype of psoriasis.86
SIRT1 is a nicotinamide adenine dinucleotide
(NAD+)-­
dependent histone deacetylase, which regulates DNA ex-
pression, cell apoptosis, and senescence through deacetylation of
substrate proteins, and participates in physiological or pathologi-
cal processes of organisms.87
SIRT1 can regulate the proliferation
and differentiation of keratinocytes in vitro, and the expression
of SIRT1 mRNA in PBMCs of patients with psoriasis is decreased,
which indicates that the excessive proliferation of keratinocytes in
patients with psoriasis may be caused by the decreased expression
of SIRT1.85
The study of the modification of abnormal histone in
psoriasis can provide a new way of thinking and direction for the
treatment of psoriasis.
4.5 | Skin development
Skin is the largest organ of the human body and covers the surface of
the human body. Its barrier function can protect the skin from inva-
sion and damage by foreign substances, while preventing the loss of
body water, electrolytes, and other substances, thereby maintain-
ing the stability of the human body and the environment.88
Skin is
composed of subcutaneous tissue, dermis, and epidermis from the
inside to the outside. The epidermis is the outermost layer of the
skin. It is in direct contact with the environment and is the natu-
ral barrier of the skin. The epidermis is divided into 5 layers from
the inside to the outside: basal layer, spinous layer, granular layer,
transparent layer, and stratum corneum.89
The skin epidermis is
differentiated from the ectoderm covering the surface of the em-
bryo. The epidermal stem cells in the basal layer of the body first
differentiate into transient expansion cells, and after multiple di-
visions, they differentiate into mitotic cells and migrate outward
and terminally differentiated cells, and then keratinization falls off
the skin surface to complete the epidermal metabolism process.
Usually, the whole process cycle is 28 days. The development and
homeostasis of the epidermis is controlled by a complex network
of sequence-­
specific transcription factors and epigenetic modifiers,
which coordinately regulate the delicate balance of progenitor cell
self-­
renewal and terminal differentiation.90
The formation and main-
tenance of the epidermis depend on the differentiation of epidermal
stem cells. Epigenetic modification plays an important role in the
development and differentiation of skin. DNMT1 is a key catalytic
enzyme in the process of DNA methylation, and it participates in
many biological processes such as stem cell growth, cell prolifera-
tion, and organ development during body development. At the same

7. | 7
HE et al.
time, DNMT1 is essential for the function of epidermal stem cells.
Studies have shown that DNMT1 protein is enriched in undifferenti-
ated skin cells, which is necessary to maintain proliferation toler-
ance and inhibit differentiation, and most epidermal differentiation
gene promoters are methylated under self-­
renewal conditions, but
then gradually demethylated during differentiation.91
The epidermal
stem cells with DNMT1 knockdown were used to regenerate human
skin on immunodeficient mice. It was found that the epidermis was
underdeveloped and prematurely differentiated, indicating that the
loss of epidermal DNMT1 is the cause of premature differentiation
and loss of tissue self-­
renewal in the epidermal stem cell-­
containing
compartment.
MYSM1 is a deubiquitinating enzyme in the human body. Its
main function is to remove the ubiquitination modification of his-
tone H2A. It plays a very important role in hematopoietic function,
immune system, skin, tissue, bone development, stem cell immune
regulation, and inflammatory factor secretion. It is a key factor for
irreplaceable epigenetic modification.92
Wilms et al.90
used Mysm1-­
deficient mice and skin-­
derived epidermal cells to systematically
analyze the expression, developmental function, and potential in-
teractions of this epigenetic regulator during skin development. It
was found that the skin of Mysm1-­
deficient mice appeared atrophic,
with reduced thickness and cells of the epidermis, dermis, and sub-
cutaneous tissue, in context with altered barrier function. At the
molecular level, p53 is a potential mediator of Mysm1-­
deficient epi-
dermal cells, leading to increased expression of pro-­
apoptotic and
anti-­
proliferative genes. Mysm1 has two functional mechanisms in
the skin development stage: (1) p53-­
mediated apoptosis is increased
in Mysm1-­
deficient skin and epidermal cells; (2) the expression of
some key transcriptional regulators of keratinocyte specifications
is changed, such as Brg1, Satb1, and Klf4. The p63-­
Brg1/Satb1-­
Klf4 axis is considered as an important developmental switch that
regulates embryonic epidermal layering and terminal keratinocyte
differentiation.93
Mysm1 is a key epigenetic regulator of epider-
mal development and epidermal stem cell regulation. It can inter-
fere with p53-­
mediated apoptosis and cell cycle inhibition, and may
change the p63 regulation program, thereby affecting the growth,
development, and differentiation of skin.
4.6 | Skin wound healing
The skin is the most important natural barrier of the human body and
the first line of defense of the human body. It plays a key role in pre-
venting mechanical forces and infections, fluid imbalances, and ther-
mal disorders. Therefore, maintaining the integrity of healthy skin
plays a vital role in maintaining the physiological homeostasis of the
human body. Many conditions lead to inadequate wound healing,
and ultimately to the loss of skin organ function, making the body
susceptible to infection, thermal disorders, and fluid loss.94
Skin
wound healing is an important step for survival in wound healing.
It is a complex process involving a series of events such as inflam-
mation, regeneration, and remodeling. It relies on the interaction of
many cell types and mediators in a highly complex time sequence.
In the process of skin injury healing, epigenetics also plays an im-
portant regulatory role. It is believed that some epigenetic changes
are achieved by interacting with bacterial products and cytokines
produced during inflammation.95
Studies have shown that epigenetic
signals play a key role in coordinating the behavior and activity of
multiple cell types during skin repair. Skin wound repair is achieved
through a dynamic and highly complex process of cell proliferation,
migration, and differentiation.96
Epidermal stem cells located in the
basal layer are an active and reproducible tissue that can change
the skin structure to maintain the skin's homeostasis, including
skin replenishment, keratinization, and shedding of old skin, hair
growth, and tissue repair after injury.97
Ezhkova et al.98
studied the
effect of epigenetic regulation in skin wound repair on the activity
of epidermal stem cells. EZH1 and EZH2 are histone lysine methyl-
transferases encoded by the EZH gene and belong to the polycomb
family protein members. The experiment conditionally controlled
the H3K27 methyltransferases EZH1 and EZH2 to understand their
role in repairing mouse skin after injury. The study found that the
loss of Ezh1 and Ezh2 slowed the closure of the epidermis due to
proliferation defects, indicating that EZH1 and EZH2 jointly control
histone H3K27 trimethylation, which is necessary for skin damage
repair. In addition to the proliferation, differentiation, and migration
of keratinocytes, the proliferation of fibroblasts in the dermis, the
formation of collagen and other matrix proteins, angiogenesis,99
and
epigenetics also play an important role in the healing process of skin
injuries. Glenisson et al.100
confirmed that HDAC4 is required for
transforming growth factor β-­1 (TgFβ-­1)-­mediated myofibroblast dif-
ferentiation. Vascular endothelial growth factor signaling is essential
for vascular morphogenesis and endothelial cell differentiation and
is attenuated by HDAC inhibition. Therefore, regulating and enhanc-
ing wound-­
healing response through epigenetic modification is re-
garded as a new and evolving field of wound management in the
healthcare system.
5 | SUMMARY AND PROSPECT
Epigenetics is gradually developed in the process of studying many
genetic phenomena that are inconsistent with the classic Mendelian
laws. Classic Mendel's law believes that phenotypic changes are
caused by DNA sequence mutations. With the deepening of re-
search, many phenotypes have changed while DNA sequences have
not changed. Epigenetics is the study of DNA methylation, histone
modification, and chromatin modification, which does not replace
the research of genetics and genomics, but opens up a new research
field as an extension of genetics.101,102
Thus, the rise of epigenet-
ics is not a scientific revolution. An important issue in epigenetics
research is the selective regulation of alleles in the same nucleus.
What mechanism distinguishes two identical alleles? What caused
the difference in the external phenotype of identical twins? What
components in the body have changed at the molecular level? How
do these changes in ingredients affect human diseases? Another

8. 8 | HE et al.
important issue in this field is the importance of the modification
of epigenetic information for the normal development of organisms.
How do these epigenetic modifications and signaling pathways be-
come disordered and lead to developmental abnormalities and can-
cer? How to prevent and treat related diseases through epigenetics?
With the deepening of research on epigenetics, epigenetics has also
been widely used in various fields and become a key research area in
the post-­
genome era.103-­105
With the rapid development of proteomics, metabolomics, and
lipidomics,106-­108
the application of these high-­
throughput, high-­
resolution technologies in skin research continues to increase.109,110
The research on different skin diseases and skin conditions has also
became more in-­depth.111,112
Revealing the material changes in these
pathological and physiological processes, especially on the molecu-
lar level, is of great significance for the prevention, treatment, and
health management of skin diseases.113-­115
The combination of epi-
genetics and multi-­
omics will further deepen our understanding of
some skin diseases, thereby improving the systematic research from
genes to proteins, and then to metabolites,116,117
and provide new
ideas for solving skin problems and developing cosmetics.
Epigenetics is closely related to human health, and epigenetic
modification is a reversible process. Once the mechanism of dis-
eases is clarified, we can use epigenetic technology to design drugs
to change or adjust the state and activity of gene expression, and
ultimately achieve control and treatment of the disease. As the
largest organ of the human body, skin has functions such as barrier
protection, hydration and moisturizing, feeling irritation, regulat-
ing body temperature, secretion, and excretion. Once the skin is
damaged or skin cancer appears, it will disturb the skin function
and affect people's normal life. Some skin diseases or skin tumors
are related to epigenetic modification.19,118
Through epigenetics,
the mechanism of some skin diseases can be studied from different
angles, and it provides new inspiration directions and theoretical
support for the research and development of cosmetics. At the
same time, the epigenetic mechanism of activating, regulating, and
silencing gene expression pathways for therapeutic regulation of
skin diseases has increasingly became the focus of clinical inter-
vention. However, this requires a deeper understanding of skin epi-
genetics and further research, so that epigenetics can make greater
contributions to the treatment of human skin diseases and reduce
skin aging.
CONFLICT OF INTEREST
The author declares that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
AUTHOR CONTRIBUTIONS
Jianbiao He searched relevant literatures and edited the manuscript.
Yan Jia provided ideas for the article and revised the manuscript.
Huaming He revised the manuscript and provided ideas for the
added parts of the article. Yufeng Qi, Jie Yang, and Leilei Zhi have
made substantial contributions to conception of epigenetic and de-
sign of the article.
ETHICS STATEMENT
All procedures performed in studies involving human participants
were in accordance with the ethical standards of the institutional
and/or national research committee and with the 1964 Helsinki dec-
laration and its later amendments or comparable ethical standards.
ORCID
Yan Jia https://orcid.org/0000-0001-5641-3478
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How to cite this article: He J, He H, Qi Y, Yang J, Zhi L, Jia Y.
Application of epigenetics in dermatological research and
skin management. J Cosmet Dermatol. 2021;00:1–­11. https://
doi.org/10.1111/jocd.14355