van Eijl Roderick A P M, van Buggenum Jessie A G L, Tanis Sabine E J, Hendriks Joost, Mulder Klaas W
Radboud University, Faculty of Science, Radboud Institute for Molecular Life Sciences, Department of Molecular Developmental Biology, Nijmegen 6525 GA, The Netherlands.
Radboud University, Faculty of Science, Radboud Institute for Molecular Life Sciences, Department of Molecular Developmental Biology, Nijmegen 6525 GA, The Netherlands.
iScience. 2018 Nov 30;9:412-422. doi: 10.1016/j.isci.2018.11.009. Epub 2018 Nov 9.
Epidermal homeostasis requires balanced and coordinated adult stem cell renewal and differentiation. These processes are controlled by both extracellular signaling and by cell intrinsic transcription regulatory networks, yet how these control mechanisms are integrated to achieve this is unclear. Here, we developed single-cell Immuno-Detection by sequencing (scID-seq) and simultaneously measured 69 proteins (including 34 phosphorylated epitopes) at single-cell resolution to study the activation state of signaling pathways during human epidermal differentiation. Computational pseudo-timing inference revealed dynamic activation of the JAK-STAT, WNT, and BMP pathways along the epidermal differentiation trajectory. We found that during differentiation, cells start producing BMP2-ligands and activate the canonical intracellular effectors SMAD1/5/9. Mechanistically, the BMP pathway is responsible for activating the MAF/MAFB/ZNF750 transcription factor network to drive late-stage epidermal differentiation. Our work indicates that incorporating signaling pathway activation into this transcription regulatory network enables coordination of transcription programs during epidermal differentiation.
表皮稳态需要成体干细胞更新和分化的平衡与协调。这些过程受细胞外信号传导和细胞内在转录调控网络的控制，但目前尚不清楚这些控制机制是如何整合以实现这一目标的。在这里，我们开发了单细胞免疫检测测序技术（scID-seq），并以单细胞分辨率同时测量了69种蛋白质（包括34个磷酸化表位），以研究人类表皮分化过程中信号通路的激活状态。计算伪时间推断揭示了JAK-STAT、WNT和BMP信号通路在表皮分化轨迹上的动态激活。我们发现，在分化过程中，细胞开始产生BMP2配体并激活经典的细胞内效应因子SMAD1/5/9。从机制上讲，BMP信号通路负责激活MAF/MAFB/ZNF750转录因子网络，以驱动晚期表皮分化。我们的工作表明，将信号通路激活纳入这一转录调控网络能够在表皮分化过程中协调转录程序。
