Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution.
Repeated mutation of a developmental enhancer contributed to human thermoregulatory evolution.
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DOI：
10.1073/pnas.2021722118
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发表时间：
2021-04-20
影响因子：
11.1
通讯作者：
Kamberov YG
中科院分区：
文献类型：
--
作者：
Aldea D;Atsuta Y;Kokalari B;Schaffner SF;Prasasya RD;Aharoni A;Dingwall HL;Warder B;Kamberov YG
人类区别于其他灵长类动物的最显著的生理特征之一是依赖出汗来降温。与其他灵长类动物相比，人类皮肤中分泌水分的外分泌汗腺的密度急剧增加，这是人类体温调节出汗的有效性的基础。在这里，我们表明，人类特异性突变在发育增强剂中的积累，通过上调皮肤中Engrailed 1转录因子的表达，共同促进了人类外分泌腺的产生。这项研究揭示了一种机制，有助于人类的签名体温调节能力的进化，并强调了调节进化在产生现代人类形态中的重要性。人类通过出汗来冷却身体，并且在灵长类动物中拥有最高的外分泌汗腺密度。人类的高外分泌腺密度一直被认为是人类进化适应的标志，但其遗传基础一直是未知的。在人类中，Engrailed 1（EN1）转录因子的表达与外分泌腺形成的开始相关。在小鼠中，外胚层En1表达的调节是菌株之间外分泌腺密度自然变化的主要决定因素，并且En1表达的增加促进了更多外分泌腺的特化。在这里，我们表明，EN1的调节已经进化到特定的人类谱系，以促进外分泌腺的形成。使用比较基因组学和小鼠外胚层增强剂活性的验证，我们鉴定了人EN1皮肤增强剂hECE 18。我们发现，在培养的角质形成细胞中，与非人猿直系同源物相比，人ECE 18增强子中的多个上位相互作用衍生的取代增加了其活性。在人培养的角质形成细胞中抑制hECE 18特异性地减弱EN 1表达，表明该元件在这种情况下正调控EN 1。在人源化增强子基因敲入小鼠中，hECE 18增加了皮肤中发育En1的表达，以诱导形成更多的外分泌腺。我们的研究揭示了一个遗传基础，有助于最奇异的人类适应之一的进化，并暗示单个增强子中的多个相互作用的突变是人类进化变化的机制。
One of the most distinctive physiological traits differentiating humans from other primates is a reliance on sweating to cool off. The effectiveness of human thermoregulatory sweating is underlain by the evolution of a dramatically increased density of water-secreting eccrine sweat glands in human skin relative to that of other primates. Here, we show that the accumulation of human-specific mutations in a developmental enhancer collectively promoted the production of eccrine glands in humans by up-regulating the expression of the Engrailed 1 transcription factor in the skin. This study reveals a mechanism that contributed to the evolution of humans’ signature thermoregulatory capabilities and underscores the importance of regulatory evolution in generating the modern human form. 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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影响因子：
64.8
作者：
Dixon JR;Jung I;Selvaraj S;Shen Y;Antosiewicz-Bourget JE;Lee AY;Ye Z;Kim A;Rajagopal N;Xie W;Diao Y;Liang J;Zhao H;Lobanenkov VV;Ecker JR;Thomson JA;Ren B
通讯作者：
Ren B
影响因子：
9.2
作者：
Barton, Robert A.;Venditti, Chris
通讯作者：
Venditti, Chris
影响因子：
--
作者：
ADELMAN, S;TAYLOR, CR;HEGLUND, NC
通讯作者：
HEGLUND, NC
影响因子：
7.3
作者：
Kleinovink, Jan Willem;Mezzanotte, Laura;Lowik, Clemens
通讯作者：
Lowik, Clemens
影响因子：
5.8
作者：
Carr, I. M.;Robinson, J. I.;Bonthron, D. T.
通讯作者：
Bonthron, D. T.