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.
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This content will become publicly available on January 1, 2025
Sweat gland development requires an eccrine dermal niche and couples two epidermal programs
Eccrine sweat glands are indispensable for human thermoregulation and, similar to other mammalian skin
appendages, form from multipotent epidermal progenitors. Limited understanding of how epidermal progen-
itors specialize to form these vital organs has precluded therapeutic efforts toward their regeneration. Herein,
we applied single-nucleus transcriptomics to compare the expression content of wild-type, eccrine-forming
mouse skin to that of mice harboring a skin-specific disruption of Engrailed 1 (En1), a transcription factor that
promotes eccrine gland formation in humans and mice. We identify two concurrent but disproportionate
epidermal transcriptomes in the early eccrine anlagen: one that is shared with hair follicles and one that is
En1 dependent and eccrine specific. We demonstrate that eccrine development requires the induction of
a dermal niche proximal to each developing gland in humans and mice. Our study defines the signatures
of eccrine identity and uncovers the eccrine dermal niche, setting the stage for targeted regeneration and
comprehensive skin repair.
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- Award ID(s):
- 1847598
- NSF-PAR ID:
- 10490635
- Publisher / Repository:
- Elsevier
- Date Published:
- Journal Name:
- Developmental Cell
- Volume:
- 59
- Issue:
- 1
- ISSN:
- 1534-5807
- Page Range / eLocation ID:
- 20 to 32.e6
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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