An Engrailed1 enhancer underlies human thermoregulatory evolution

SummaryHumans rely on sweating to cool off and have the highest eccrine sweat gland density among mammals. We investigated whether altered regulation of the Engrailed 1 (EN1) gene, the levels of which are critical for patterning eccrine glands during development, could underlie the evolution of this defining human trait. First, we identify five EN1 candidate enhancers (ECEs) using comparative genomics and validation of enhancer activity in mouse skin. The human ortholog of one ECE, hECE18, contains multiple derived substitutions that together dramatically increase the activity of this enhancer in keratinocytes. Targeted repression of hECE18 reduces EN1 expression in human keratinocytes, indicating hECE18 upregulates EN1 in this context. Finally, we find that hECE18 increases ectodermal En1 in a humanized knock-in mouse to increase eccrine gland number. Our study uncovers a genetic basis for the evolution of one of the most singular human adaptations and implicates the recurrent mutation of a single enhancer as a novel mechanism for evolutionary change.

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Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021722118 ◽

2021 ◽

Vol 118 (16) ◽

pp. e2021722118

Author(s):

Daniel Aldea ◽

Yuji Atsuta ◽

Blerina Kokalari ◽

Stephen F. Schaffner ◽

Rexxi D. Prasasya ◽

...

Keyword(s):

Transcription Factor ◽

Natural Variation ◽

Genetic Basis ◽

Eccrine Sweat Gland ◽

Evolutionary Adaptation ◽

Human Lineage ◽

Eccrine Gland ◽

Enhancer Activity ◽

Cultured Keratinocytes ◽

Eccrine Glands

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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A genetic basis of variation in eccrine sweat gland and hair follicle density

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511680112 ◽

2015 ◽

Vol 112 (32) ◽

pp. 9932-9937 ◽

Cited By ~ 26

Author(s):

Yana G. Kamberov ◽

Elinor K. Karlsson ◽

Gerda L. Kamberova ◽

Daniel E. Lieberman ◽

Pardis C. Sabeti ◽

...

Keyword(s):

Hair Follicle ◽

Genetic Regulation ◽

Eccrine Sweat Gland ◽

Hair Follicles ◽

The Body ◽

Chromosome 1 ◽

Sweat Glands ◽

Eccrine Gland ◽

Eccrine Glands ◽

Eccrine Sweat

Among the unique features of humans, one of the most salient is the ability to effectively cool the body during extreme prolonged activity through the evapotranspiration of water on the skin’s surface. The evolution of this novel physiological ability required a dramatic increase in the density and distribution of eccrine sweat glands relative to other mammals and a concomitant reduction of body hair cover. Elucidation of the genetic underpinnings for these adaptive changes is confounded by a lack of knowledge about how eccrine gland fate and density are specified during development. Moreover, although reciprocal changes in hair cover and eccrine gland density are required for efficient thermoregulation, it is unclear if these changes are linked by a common genetic regulation. To identify pathways controlling the relative patterning of eccrine glands and hair follicles, we exploited natural variation in the density of these organs between different strains of mice. Quantitative trait locus mapping identified a large region on mouse Chromosome 1 that controls both hair and eccrine gland densities. Differential and allelic expression analysis of the genes within this interval coupled with subsequent functional studies demonstrated that the level of En1 activity directs the relative numbers of eccrine glands and hair follicles. These findings implicate En1 as a newly identified and reciprocal determinant of hair follicle and eccrine gland density and identify a pathway that could have contributed to the evolution of the unique features of human skin.

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Ultraviolet (UV) B radiation causes an upregulation of Survivin in human keratinocytes and mouse skin

Photochemistry and Photobiology ◽

10.1562/2004-08-18-rc-280 ◽

2004 ◽

Author(s):

Moammir Hasan Aziz ◽

Amaninderpal S. Ghotra ◽

Yogeshwer Shukla ◽

Nihal Ahmad

Keyword(s):

Mouse Skin ◽

Human Keratinocytes

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Manganese Superoxide Dismutase-Mediated Inside-Out Signaling in HaCaT Human Keratinocytes and SKH-1 Mouse Skin

Antioxidants and Redox Signaling ◽

10.1089/ars.2013.5204 ◽

2014 ◽

Vol 20 (15) ◽

pp. 2347-2360 ◽

Cited By ~ 16

Author(s):

Aaron K. Holley ◽

Yong Xu ◽

Teresa Noel ◽

Vasudevan Bakthavatchalu ◽

Ines Batinic-Haberle ◽

...

Keyword(s):

Superoxide Dismutase ◽

Manganese Superoxide Dismutase ◽

Mouse Skin ◽

Human Keratinocytes ◽

Manganese Superoxide ◽

Inside Out

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Differential Expression of a Cutaneous Corticotropin-Releasing Hormone System

Endocrinology ◽

10.1210/en.2003-0851 ◽

2004 ◽

Vol 145 (2) ◽

pp. 941-950 ◽

Cited By ~ 126

Author(s):

Andrzej Slominski ◽

Alexander Pisarchik ◽

Desmond J. Tobin ◽

Joseph E. Mazurkiewicz ◽

Jacobo Wortsman

Keyword(s):

Human Skin ◽

Expression Patterns ◽

Mouse Skin ◽

Hair Follicles ◽

Dermal Fibroblasts ◽

Preferential Expression ◽

Eccrine Glands ◽

Species Specific ◽

Skin Function ◽

Human And Mouse

Abstract We completed the mapping of a cutaneous CRH signaling system in two species with widely different determinants of skin functions, humans and mice. In human skin, the CRH receptor (CRH-R) 1 was expressed in all major cellular populations of epidermis, dermis, and subcutis with CRH-R1α being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels. In mouse skin, the CRH-R2 gene and protein were widely expressed in all cutaneous compartments and in cultured normal and malignant melanocytes. CRH-binding protein mRNA was present in dermal fibroblasts, melanoma cells, and sc fat of human skin and undetectable in mouse skin. The urocortin II gene was expressed equally in mouse and human skin. Taken together with our previous investigations, the present studies document the preferential expression of CRH-R1 in human skin, which mirrors CRH-R2 expression patterns in human and mouse skin. They are likely reflecting different functional activities of human and mouse skin. The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants.

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Digital Papillary Adenocarcinoma: Case of a Rare Malignant Cutaneous Tumor of the Eccrine Sweat Gland

Case Reports in Dermatology ◽

10.1159/000518442 ◽

2021 ◽

pp. 422-427

Author(s):

Austin J. Jabbour ◽

Ibrahim A. Tangoren ◽

Andrew B. Kanik

Keyword(s):

Treatment Strategies ◽

Specific Treatment ◽

Papillary Adenocarcinoma ◽

Eccrine Sweat Gland ◽

Sweat Glands ◽

High Concentration ◽

Eccrine Glands ◽

Cutaneous Tumor ◽

Hands And Feet ◽

Eccrine Sweat

Digital papillary adenocarcinoma (DPA) is a rare cutaneous tumor originating from the eccrine sweat glands. These lesions occur almost exclusively on the digits of the hands and feet, where there is a high concentration of eccrine glands. The diagnosis is made histologically, and the course of the malignancy tends to be very aggressive with high rates of recurrence and early metastasis at the time of diagnosis. Due to the low incidence of these lesions, there have been minimal objective data from clinical studies to recommend specific treatment strategies. Wide local excision versus digital amputation proximal to the lesion has been debated for primary treatment, while there are no data to support routine implementation of adjuvant chemotherapy or radiation, despite its metastatic nature. This article presents a case of long-standing, previously undiagnosed DPA. The lesion appeared more inconspicuous on gross examination than other reports in the literature, and diagnosis was made with punch biopsy and confirmed postsurgically. To date, the patient has not had recurrence, although she is being monitored for potential metastatic deposits in her lungs. Clinical dermatologists should be aware of the high mortality burden this lesion may inflict if left undiagnosed or mistreated.

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