HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity.

Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1, Krt16, and Aqp3 In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.

The Psychosocial Impact of Atopic Dermatitis.

Atopic dermatitis is a chronic skin condition that has significant psychosocial and quality-of-life impact. The condition causes physical discomfort, emotional distress, embarrassment, social stigma, and daily activity limitation. In an effort to assess these aspects of disease burden, quality-of-life measurement tools were developed. Through use of these tools, we have expanded our knowledge of the psychosocial and quality-of-life burden of this condition. A variety of quality of assessment tools exist, yet there is no consensus on which tool is best suited to assess the quality-of-life impact of atopic dermatitis. Research studies assessing quality-of-life in atopic dermatitis patients utilize a variety of quality-of-life measurement tools; this complicates comparisons across research studies. Though comparison across studies is difficult, the data echoes tremendous overall burden of disease, especially pertaining to psychosocial status and life quality.

The Psychosocial Impact of Atopic Dermatitis.

Atopic dermatitis is a chronic skin condition which has significant psychosocial and quality of life impact. The condition causes physical discomfort, emotional distress, embarrassment, social stigma and daily activity limitation. In an effort to assess these aspects of disease burden, quality of life measurement tools were developed. Through use of these tools, we have expanded our knowledge of the psychosocial and quality of life burden of this condition. A variety of quality of life assessment tools exist, yet there is no consensus on which tool is best suited to assess the quality of life impact of atopic dermatitis. Research studies assessing quality of life in atopic dermatitis patients utilize a variety of quality of life measurement tools; this complicates comparisons across research studies. Though comparison across studies is difficult, the data echoes tremendous overall burden of disease, especially pertaining to psychosocial status and life quality.

Regional Control of Hairless versus Hair-Bearing Skin by Dkk2.

Haired skin is a defining characteristic of mammals. However, some specialized skin regions, such as human palms, soles and ventral wrist, and mouse plantar foot, are entirely hairless. Using mouse plantar skin as a model system, we show that the endogenous secreted Wnt inhibitor DKK2 suppresses plantar hair follicle development and permits the formation of hairless skin. Plantar skin retains all of the mechanistic components needed for hair follicle development, as genetic deletion of Dkk2 permits formation of fully functional plantar hair follicles that give rise to external hair, contain sebaceous glands and a stem cell compartment, and undergo regenerative growth. In the absence of Dkk2, Wnt/ß-catenin signaling activity is initially broadly elevated in embryonic plantar skin and gradually becomes patterned, mimicking follicular development in normally haired areas. These data provide a paradigm in which regionally restricted expression of a Wnt inhibitor underlies specification of hairless versus hairy skin.

Uncommon Filaggrin Variants Are Associated with Persistent Atopic Dermatitis in African Americans.

Atopic dermatitis (AD) is a common illness that has been associated with filaggrin gene (FLG) loss of function (LoF) variation. In African Americans, a group that commonly has AD and has not been well studied, FLG LoF variation is rarely found. Our objective was to use massively parallel sequencing to evaluate FLG LoF variation in children of African ancestry to evaluate the association between FLG LoF variation and AD and AD persistence. We studied 262 African American children with AD. Nine unique FLG exon 3 LoF variants were identified for an overall minor variant frequency of 6.30% (95% confidence interval [CI] = 4.37-8.73). The most common variants were p.R501X (1.72%, 95% CI = 0.79-3.24), p.S3316X (1.34%, 95% CI = 0.54-2.73), and p.R826X (0.95%, 95% CI = 0.31-2.2). Over an average follow-up period of 96.4 (95% CI = 92.0-100.8) months, African American children with FLG LoF were less likely to be symptom free (odds ratio = 0.36, 95% CI = 0.14-0.89, P = 0.027) compared with a FLG wild-type child. In contrast to previous reports, uncommon FLG LoF variants in African American children exist and are associated with AD and more persistent AD. In contrast to Europeans, no FLG LoF variants predominate in African American children. Properly determining FLG LoF status requires advanced sequencing techniques.

WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation.

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that ß-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that ß-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream ß-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.