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Novel role of cholesterol sulfate in gene regulation during skin development
Author(s) -
Nakae Hanako,
Hanyu Osamu,
Fuda Hirotoshi,
Strott Charles A
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.782.2
Subject(s) - filaggrin , gene knockdown , epidermis (zoology) , nuclear receptor , retinoic acid , chemistry , microbiology and biotechnology , gene expression , messenger rna , receptor , keratinocyte , transcription factor , gene , biology , biochemistry , immunology , atopic dermatitis , anatomy , in vitro
Cholesterol sulfate (CS) is prominent in the epidermis where it accumulates during skin development. Cholesterol sulfotransferase (SULT2B1b), which produces CS localizes to the granular layer of the epidermis coinciding with the highest CS content. Localization of SULT2B1b is similar to that of the barrier protein filaggrin, a late marker of keratinocyte differentiation. CS, based on crystallographic data, binds with high affinity to the retinoic acid receptor‐related orphan receptor alpha (RORα) moreover, binding translates into increased transcriptional activity. Using normal human epidermal keratinocytes (NHEK) in primary culture, CS stimulates profilaggrin (filaggrin precursor protein) mRNA expression in a dose‐dependent manner, and hypothesized that CS by binding to the nuclear receptor RORα stimulates profilaggrin gene transcription. This hypothesis was tested by knockdown experiments directed against mRNAs for RORα and SULT2B1b using NHEK during calcium‐induced differentiation. Concomitant with siRNA‐induced reduction in either RORα or SULT2B1b expression, a decrease in profilaggrin mRNA expression of up to 80% was observed. Furthermore, during RORα knockdown CS was unable to stimulate profilaggrin mRNA expression. These studies suggest that CS regulates the gene for profilaggrin via its ability to interact with the nuclear receptor RORα, an action reminiscent of a typical hormone.