Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression.
Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression.
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DOI：
10.1016/j.stem.2017.12.004
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发表时间：
2018-03-01
期刊：
影响因子：
23.9
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Adam RC;Yang H;Ge Y;Lien WH;Wang P;Zhao Y;Polak L;Levorse J;Baksh SC;Zheng D;Fuchs E
组织再生依赖于驻留干细胞，其活性和谱系选择受微环境的影响。利用毛囊中同步的、周期性的组织再生，我们研究了微环境动力学如何塑造SC谱系的出现。利用表观遗传学和芯片序列分析，我们揭示了信号依赖的转录因子如何将时空线索耦合到染色质动态，从而编排SC谱系。利用增强子驱动的记者、突变和遗传学，我们证明了同时的BMP抑制信号和WNT信号通过建立允许多样化的染色质平台为谱系选择奠定了基础。从机制上讲，当BMP-效应器pSMAD1的结合解除时，驱动HF-SC主调控子的增强子被沉默。随之而来的是，在HF-SCs中沉默的多能、血统注定的增强子通过将WNT效应器TCF3/4替换为LEF1而被激活。在整个再生过程中，谱系增强剂继续依赖LEF1，但随后通过容纳更多的传入信号效应器来实现特异性。当不同的、信号敏感的转录因子形成LEF1调节的增强子动态时，祖细胞可塑性的障碍增加。外部信号如何与染色质相互作用，使干细胞沿着不同的组织谱系计划进行，仍然是一个谜。在这里，亚当等人。结合表观基因组、遗传学、单细胞转录组和染色质传感器数据，展示如何通过在已建立的染色质平台上对信号效应器进行时间分层来获得新的命运。
Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of SC lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatio-temporal cues to chromatin dynamics, thereby choreographing SC lineages. Using enhancer-driven reporters, mutagenesis and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP-effector pSMAD1 is relieved, enhancers driving HF-SC master regulators are silenced. Concomitantly, multipotent, lineage-fated enhancers silent in HF-SCs become activated by exchanging WNT-effectors TCF3/4 for LEF1. Throughout regeneration, lineage enhancers continue reliance upon LEF1, but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity increase when diverse, signal-sensitive transcription factors shape LEF1-regulated enhancer dynamics. How external signals interface with chromatin to coax stem cells along distinct tissue lineage programs remains a mystery. Here, Adam et al. combine epigenomic, genetic, single cell transcriptome and chromatin sensor data to show how new fates are acquired through temporal layering of signaling effectors atop established chromatin platforms.
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影响因子：
64.5
作者：
Hsu YC;Pasolli HA;Fuchs E
通讯作者：
Fuchs E
Tcf3可抑制Wnt-β-catenin信号，并在新皮质发育过程中维持神经干细胞的数量。
影响因子：
3.7
作者：
Kuwahara A;Sakai H;Xu Y;Itoh Y;Hirabayashi Y;Gotoh Y
通讯作者：
Gotoh Y
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
DOI：
10.1126/science.1242281
发表时间：
2014-06-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Blanpain C;Fuchs E
通讯作者：
Fuchs E
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK