Abstract
Terminal differentiation of skin keratinocytes is a vertically directed multi-step process that is tightly controlled by the sequential expression of a variety of genes. In this study, we investigated the role of the POU domain-containing transcription factor Brn2 in keratinocyte differentiation. Immunohistochemical analysis showed that Brn2 is expressed primarily in the upper granular layer. Consistent with its epidermal localization, Brn2 expression was highly induced at 14 days after calcium treatment of cultured normal human epidermal keratinocytes. When Brn2 was overexpressed by adenoviral transduction, Brn2 led to increased expression of the differentiation-related genes involucrin, filaggrin, and loricrin in addition to inhibition of their proliferation. Chromatin immunoprecipitation demonstrated that Brn2 bound to the promoter regions of these differentiation-related genes. We injected the purified Brn2 adenovirus into rat skin, which led to a thickened epidermis with increased amounts of differentiation related markers. The histopathologic features of adenovirus-Brn2 injected skin tissues looked similar to the features of lichen planus, a human skin disease showing chronic inflammation and well-differentiated epidermal changes. Moreover, Brn2 is shown to be expressed in almost all cell nuclei of the thickened epidermis of lichen planus, and Brn2 also attracts T lymphocytes. Our results demonstrate that Brn2 is probably a transcriptional factor playing an important role in keratinocyte differentiation and probably also in the pathogenesis of lichen planus lesions.
Highlights
Terminal differentiation of skin keratinocytes, in which the transition from basal keratinocytes to corneocytes is occurred, is a complex process that requires the simultaneous activation and inactivation of a wide variety of genes that must be expressed at the correct time and in the correct location [1]
Since the expression of Brn2 was increased in the granular layer of the epidermis as well as in the differentiated keratinocytes by calcium, we speculated that Brn2 has a role for keratinocyte differentiation
To determine whether Brn2 effect was at the promoter level, we transduced keratinocytes with involucrin-luc reporter adenoviruses, in which about 3.7 kb of involucrin promoter fragment was fused to luciferase gene
Summary
Terminal differentiation of skin keratinocytes, in which the transition from basal keratinocytes to corneocytes is occurred, is a complex process that requires the simultaneous activation and inactivation of a wide variety of genes that must be expressed at the correct time and in the correct location [1]. A number of ubiquitous transcription factors, such as AP1, Sp1, and the AP2 family members, are involved in regulating keratinocyte gene expression and differentiation [3]. We identify a POU domain-containing transcription factor Brn as an important regulator in keratinocyte differentiation. POU domain proteins have been implicated in development, replication, growth and cell cycle arrest, and differentiation [4,5,6]. POU domain-containing transcription factor Brn ( called N-Oct and POU3F2) has been implicated in both neuronal differentiation and activation of the corticotrophinreleasing hormone gene [7,8,9]. As for skin cells, evidence implicates it in melanoma growth and survival. The expression and putative role of Brn in keratinocytes have not been clearly elucidated yet
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