Abstract
More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB risk locus on chromosome (chr.) 2q35, where we have previously reported a regulatory effect of the MPB lead variant on the expression of WNT10A. A HaploReg database research for regulatory annotations revealed that the association signal at 2q35 maps to a binding site for the transcription factor EBF1, whose gene is located at a second MPB risk locus on chr. 5q33.3. To investigate a potential interaction between EBF1 and WNT10A during MPB development, we performed in vitro luciferase reporter assays as well as expression analyses and immunofluorescence co-stainings in microdissected human hair follicles. Our experiments confirm that EBF1 activates the WNT10A promoter and that the WNT10A/EBF1 interaction is impacted by the allelic expression of the MPB risk allele at 2q35. Expression analyses across different hair cycle phases and immunhistochemical (co)stainings against WNT10A and EBF1 suggest a predominant relevance of EBF1/WNT10A interaction for hair shaft formation during anagen. Based on these findings we suggest a functional mechanism at the 2q35 risk locus for MPB, where an MPB-risk allele associated reduction in WNT10A promoter activation via EBF1 results in a decrease in WNT10A expression that eventually results in anagen shortening, that is frequently observed in MPB affected hair follicles. To our knowledge, this study is the first follow-up study on MPB that proves functional interaction between two MPB risk loci and sheds light on the underlying pathophysiological mechanism at these loci.
Highlights
Male-pattern baldness (MPB) is the most common form of heritable hair loss in men
Subsequent in silico analyses predicted an MPB risk allele dependent change in EBF1 binding affinity to its target site within WNT10A. These findings led us to hypothesize that the MPB risk loci on 2q35 and 5q33.3 are functionally connected through EBF1, which acts as a regulator of WNT10A expression in the control of hair growth cycling
Our experimental analyses using in vitro cell culture models and luciferase assays revealed that EBF1 is able to induce gene expression via the WNT10A promoter, where WNT10A promoter activation is positively correlated with EBF1 stimulation
Summary
Male-pattern baldness (MPB) is the most common form of heritable hair loss in men. The phenotype is characterized by an androgen-dependent progressive hair loss in distinct areas of the scalp. While the pathophysiological signs have been well described (reviewed elsewhere [1]), the molecular mechanisms that underlie the patterned hair loss remain elusive. Functional interaction of EBF1 and WNT10A in male-pattern baldness
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