The time-resolved genomic impact of Wnt/β-catenin signaling.

IF 9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Systems Pub Date : 2023-07-01 DOI:10.2139/ssrn.4208342
P. Pagella, Simon Söderholm, A. Nordin, Gianluca Zambanini, Valeria Ghezzi, Amaia Jauregi-Miguel, C. Cantú
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引用次数: 4

Abstract

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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Wnt/β-catenin信号传导的时间分辨基因组影响。
Wnt信号通过其效应子β-连环蛋白协调基因表达。然而,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以调节细胞行为。使用针对β-连环蛋白的时间分辨CUT和RUN、ATAC-seq和不同细胞类型的扰动分析相结合,我们发现Wnt/β-连环素物理靶标是组织特异性的,β-连环肽随着时间的推移在不同的基因座上“移动”,其与DNA的关联伴随着决定细胞行为的染色质可及性景观的变化。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-caten驱动短暂的染色质开放,然后重新建立预刺激状态,我们将其定义为“弹性”的反应。“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、细胞特性和染色质限制的支配。补充信息中包含了本文透明同行评审过程的记录。
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来源期刊
Cell Systems
Cell Systems Medicine-Pathology and Forensic Medicine
CiteScore
16.50
自引率
1.10%
发文量
84
审稿时长
42 days
期刊介绍: In 2015, Cell Systems was founded as a platform within Cell Press to showcase innovative research in systems biology. Our primary goal is to investigate complex biological phenomena that cannot be simply explained by basic mathematical principles. While the physical sciences have long successfully tackled such challenges, we have discovered that our most impactful publications often employ quantitative, inference-based methodologies borrowed from the fields of physics, engineering, mathematics, and computer science. We are committed to providing a home for elegant research that addresses fundamental questions in systems biology.
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