CDK12 Is Necessary to Promote Epidermal Differentiation Through Transcription Elongation.
CDK12 Is Necessary to Promote Epidermal Differentiation Through Transcription Elongation.
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CDK12 对于通过转录延伸促进表皮分化是必需的。
DOI：
10.1093/stmcls/sxac002
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Sen,GeorgeL
中科院分区：
文献类型：
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作者：
Li,Jingting;Tiwari,Manisha;Chen,Yifang;Luanpitpong,Sudjit;Sen,GeorgeL
表皮的适当分化对于防止水分流失和保护身体免受外界环境的影响至关重要。这一过程的干扰可能会导致各种皮肤病，影响五分之一的人。虽然控制表皮分化的转录因子已得到很好的表征，但转录控制的其他方面（例如伸长）却知之甚少。在这里，我们表明，在已知调节转录延伸的两种细胞周期蛋白依赖性激酶（CDK12 和 CDK13）中，只有 CDK12 是表皮分化所必需的。 CDK12 的耗竭导致分化基因表达丧失以及再生人表皮中皮肤屏障形成的缺失。 CDK12 与编码促进分化的转录因子（GRHL3、KLF4 和 OVOL1）的基因结合，并且是其延伸所必需的。 CDK12 通过促进 RNA 聚合酶 II C 末端结构域上的 Ser2 磷酸化以及稳定延伸因子 SPT6 与靶基因的结合，对于延伸是必需的。我们的结果表明 CDK12 对转录延伸的控制在成体细胞命运决定中发挥着重要作用。
Proper differentiation of the epidermis is essential to prevent water loss and to protect the body from the outside environment. Perturbations in this process can lead to a variety of skin diseases that impacts 1 in 5 people. While transcription factors that control epidermal differentiation have been well characterized, other aspects of transcription control such as elongation are poorly understood. Here we show that of the two cyclin-dependent kinases (CDK12 and CDK13), that are known to regulate transcription elongation, only CDK12 is necessary for epidermal differentiation. Depletion of CDK12 led to loss of differentiation gene expression and absence of skin barrier formation in regenerated human epidermis. CDK12 binds to genes that code for differentiation promoting transcription factors (GRHL3,KLF4, andOVOL1) and is necessary for their elongation. CDK12 is necessary for elongation by promoting Ser2 phosphorylation on the C-terminal domain of RNA polymerase II and the stabilization of binding of the elongation factor SPT6 to target genes. Our results suggest that control of transcription elongation by CDK12 plays a prominent role in adult cell fate decisions.