The time-resolved genomic impact of Wnt/β-catenin signaling.
The time-resolved genomic impact of Wnt/β-catenin signaling.
复制标题
Wnt/β-连环蛋白信号传导的时间分辨基因组影响。
作者：
P. Pagella;Simon Söderholm;A. Nordin;Gianluca Zambanini;Valeria Ghezzi;Amaia Jauregi;C. Cantú
Wnt信号通过其效应物β-连环蛋白协调基因表达。然而，目前尚不清楚β-连环蛋白是否同时结合其靶基因组区域，以及这如何影响染色质动力学来调节细胞行为。通过对不同细胞类型的β-catenin进行时间分辨的cut和run、ATAC-seq和扰动分析，我们发现Wnt/β-catenin的物理靶标是组织特异性的，β-catenin随着时间的推移在不同的位点上“移动”，并且它与DNA的关联伴随着染色质可及性的变化，从而决定细胞的行为。特别是，Wnt/β-catenin在人类胚胎干细胞（hESCs）经历中胚层分化时逐渐形成染色质，我们将这种行为定义为“可塑性”。另一方面，在HEK293T细胞中，Wnt/β-catenin驱动短暂的染色质打开，随后重建预刺激状态，我们将这种反应定义为“弹性”。未来的实验将评估除了Wnt信号外，其他细胞通讯机制是否受时间、细胞特质和染色质限制的支配。本文的透明同行评议过程记录包含在补充信息中。
Wnt signaling orchestrates gene expression via its effector, β-catenin. However, it is unknown whether β-catenin binds its target genomic regions simultaneously and how this impacts chromatin dynamics to modulate cell behavior. Using a combination of time-resolved CUT&RUN against β-catenin, ATAC-seq, and perturbation assays in different cell types, we show that Wnt/β-catenin physical targets are tissue-specific, β-catenin "moves" on different loci over time, and its association to DNA accompanies changing chromatin accessibility landscapes that determine cell behavior. In particular, Wnt/β-catenin progressively shapes the chromatin of human embryonic stem cells (hESCs) as they undergo mesodermal differentiation, a behavior that we define as "plastic." In HEK293T cells, on the other hand, Wnt/β-catenin drives a transient chromatin opening, followed by re-establishment of the pre-stimulation state, a response that we define as "elastic." Future experiments shall assess whether other cell communication mechanisms, in addition to Wnt signaling, are ruled by time, cellular idiosyncrasies, and chromatin constraints. A record of this paper's transparent peer review process is included in the supplemental information.
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影响因子：
10.5
作者：
Cole, Megan F.;Johnstone, Sarah E.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
7.2
作者：
MacDonald, Bryan T.;He, Xi
通讯作者：
He, Xi
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
影响因子：
64.5
作者：
Marks H;Kalkan T;Menafra R;Denissov S;Jones K;Hofemeister H;Nichols J;Kranz A;Stewart AF;Smith A;Stunnenberg HG
通讯作者：
Stunnenberg HG