Humans sweat to cool their bodies and have by far the highest eccrine sweat gland density among primates. Humans’ high eccrine gland density has long been recognized as a hallmark human evolutionary adaptation, but its genetic basis has been unknown. In humans, expression of the Engrailed 1 (EN1) transcription factor correlates with the onset of eccrine gland formation. In mice, regulation of ectodermal En1 expression is a major determinant of natural variation in eccrine gland density between strains, and increased En1 expression promotes the specification of more eccrine glands. Here, we show that regulation of EN1 has evolved specifically on the human lineage to promote eccrine gland formation. Using comparative genomics and validation of ectodermal enhancer activity in mice, we identified a human EN1 skin enhancer, hECE18. We showed that multiple epistatically interacting derived substitutions in the human ECE18 enhancer increased its activity compared with nonhuman ape orthologs in cultured keratinocytes. Repression of hECE18 in human cultured keratinocytes specifically attenuated EN1 expression, indicating this element positively regulates EN1 in this context. In a humanized enhancer knock-in mouse, hECE18 increased developmental En1 expression in the skin to induce the formation of more eccrine glands. Our study uncovers a genetic basis contributing to the evolution of one of the most singular human adaptations and implicates multiple interacting mutations in a single enhancer as a mechanism for human evolutionary change.
Eccrine glands are mammalian skin appendages indispensable for human thermoregulation. Like all skin-derived appendages, eccrine glands form from multipotent progenitors in the basal skin epidermis. It remains unclear how epidermal progenitors progressively specialize to specifically form eccrine glands, precluding efforts to regenerate these vital organs. Herein, we applied single nucleus transcriptomics to compare the expression content of wildtype, eccrine-forming mouse skin to that of mice harboring a skin-specific disruption ofEngrailed 1(En1), a transcription factor that promotes the formation of eccrine glands in both humans and mice. We identify two concurrent epidermal transcriptomes in the earliest eccrine anlagen: a predominant transcriptome that is shared with hair follicles, and a vastly underrepresented transcriptome that isEn1-dependent and eccrine-specific. We demonstrate that differentiation of the eccrine anlage requires the induction of a transient and transcriptionally unique dermal niche that forms around each developing gland in humans and mice. Our study defines the transcriptional determinants underlying eccrine identity in the epidermis and uncovers the dermal niche required for eccrine developmental progression. By identifying these defining components of the eccrine developmental program, our findings set the stage for directed efforts to regenerate eccrine glands for comprehensive skin repair.
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