Ann Dermatol.  2020 Apr;32(2):122-129. 10.5021/ad.2020.32.2.122.

Epigenetic Regulation of Filaggrin Gene Expression in Human Epidermal Keratinocytes

Affiliations
  • 1Bio-Integration Research Center for Nutra-Pharmaceutical Epigenetics, Chung-Ang University, Seoul, Korea. uromyung@cau.ac.kr
  • 2Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea.
  • 3Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND
Loss-of-function mutations in the filaggrin gene (FLG), which encodes an epidermal protein crucial for the formation of a functional skin barrier, have been identified as a major predisposing factor in the etiopathogenesis of atopic dermatitis (AD). Recent reports of relatively low frequencies of FLG-null mutations among specific ethnic groups with AD necessitated analysis of the epigenetic regulation which may control FLG expression without altering its DNA sequence.
OBJECTIVE
The study aimed to identify DNA methylation-dependent regulation of FLG expression.
METHODS
Quantitative polymerase chain reaction was performed to determine the restoration of FLG mRNA expression in normal human epidermal keratinocyte (NHEK) cells after treatment with epigenetic modulating agents. Bisulfite genomic sequencing and pyrosequencing analyses of the FLG promoter region were conducted to identify the citical CpG sites relevant to FLG expression. We performed small-scale pilot study for epidermal tissues obtained from Korean patients with severe AD.
RESULTS
We here show that DNA methylation in the FLG with non-CpG island promoter is responsible for the transcriptional regulation of FLG in undifferentiated NHEK cells. The methylation frequencies in a single CpG site of the FLG promoter were significantly higher in lesional epidermis than those in matched nonlesional epidermis of subjects with severe AD.
CONCLUSION
Our in vitro and clinical studies point to this unique CpG site as a potential DNA methylation marker of FLG, which can be a promising therapeutic target in the complications of filaggrin-related skin barrier dysfunction as well as in AD.

Keyword

Atopic dermatitis; DNA methylation; Keratinocyte

MeSH Terms

Base Sequence
Causality
Dermatitis, Atopic
DNA
DNA Methylation
Epidermis
Epigenomics*
Ethnic Groups
Gene Expression*
Humans*
In Vitro Techniques
Keratinocytes*
Methylation
Pilot Projects
Polymerase Chain Reaction
Promoter Regions, Genetic
RNA, Messenger
Skin
DNA
RNA, Messenger
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