小柯机器人

RIPK4-IRF6信号轴调控表皮分化
2019-10-03 20:31

美国基因泰克公司Vishva M. Dixit团队的最新研究发现RIPK4-IRF6信号轴可确保表皮分化和屏障功能。相关论文2019年10月2日在线发表于《自然》杂志。

研究人员证明RIPK4在小鼠发育中的作用需要其激酶活性。表皮中表达的RIPK4和IRF6调节相同的生物学过程;并且IRF6在第413位丝氨酸和第424位丝氨酸处的磷酸化引发了IRF6的激活。使用RNA测序(RNA-seq)、组蛋白染色质免疫沉淀后测序(ChIP-seq),并使用野生型和IRF6缺陷型小鼠胚胎皮肤的测序(ATAC-seq)测定转座酶可及的染色质,研究人员定义了在表皮分化过程中受IRF6调控的转录程序。IRF6在二价启动子上富集,而IRF6缺乏导致与脂质代谢和紧密连接形成有关的基因表达缺陷。因此,Irf6基因缺失皮肤角质层的脂质组成异常,最终导致表皮屏障功能的严重缺陷。

总的来说,这些结果解释了RIPK4和IRF6如何发挥功能以确保表皮的完整性,并提供了机制上的见解,以解释为什么当该信号轴出现偏差时会导致以口面部、皮肤和生殖器异常为特征的发育综合征。

据了解,哺乳动物表皮的完整性取决于干细胞常驻群体中增殖与分化之间的平衡。激酶RIPK4和转录因子IRF6在人类严重发育综合症中发生突变,缺乏这些基因的小鼠表现出表皮过度增殖和软组织融合,导致新生小鼠死亡。人们对这些基因如何控制表皮分化的理解还不完全。

附:英文原文

Title: The RIPK4–IRF6 signalling axis safeguards epidermal differentiation and barrier function

Author: Nina Oberbeck, Victoria C. Pham, Joshua D. Webster, Rohit Reja, Christine S. Huang, Yue Zhang, Merone Roose-Girma, Sren Warming, Qingling Li, Andrew Birnberg, Weng Wong, Wendy Sandoval, Lszl G. Kmves, Kebing Yu, Debra L. Dugger, Allie Maltzman, Kim Newton, Vishva M. Dixit

Issue&Volume: 2019-10-02

Abstract: 

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2,3,4,5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP–seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6−/− skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.

DOI: 10.1038/s41586-019-1615-3

Source: https://www.nature.com/articles/s41586-019-1615-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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