Afouda Boni A, Nakamura Yukio, Shaw Sophie, Charney Rebekah M, Paraiso Kitt D, Blitz Ira L, Cho Ken W Y, Hoppler Stefan
Institute of Medical Sciences, Foresterhill Health Campus, University of Aberdeen, ABERDEEN AB25 2ZD Scotland, UK.
Centre for Genome Enabled Biology and Medicine, Old Aberdeen Campus, University of Aberdeen, ABERDEEN AB24 2FX Scotland, UK.
iScience. 2020 Jul 24;23(7):101314. doi: 10.1016/j.isci.2020.101314. Epub 2020 Jun 25.
Although Wnt/β-catenin signaling is generally conserved and well understood, the regulatory mechanisms controlling context-specific direct Wnt target gene expression in development and disease are still unclear. The onset of zygotic gene transcription in early embryogenesis represents an ideal, accessible experimental system to investigate context-specific direct Wnt target gene regulation. We combine transcriptomics using RNA-seq with genome-wide β-catenin association using ChIP-seq to identify stage-specific direct Wnt target genes. We propose coherent feedforward regulation involving two distinct classes of direct maternal Wnt target genes, which differ both in expression and persistence of β-catenin association. We discover that genomic β-catenin association overlaps with Foxh1-associated regulatory sequences and demonstrate that direct maternal Wnt target gene expression requires Foxh1 function and Nodal/Tgfβ signaling. Our results support a new paradigm for direct Wnt target gene co-regulation with context-specific mechanisms that will inform future studies of embryonic development and more widely stem cell-mediated homeostasis and human disease.
尽管Wnt/β-连环蛋白信号通路通常是保守的且已被充分理解，但在发育和疾病中控制特定背景下直接Wnt靶基因表达的调控机制仍不清楚。早期胚胎发生中合子基因转录的起始代表了一个理想的、易于研究的实验系统，用于研究特定背景下直接Wnt靶基因的调控。我们将使用RNA测序的转录组学与使用ChIP测序的全基因组β-连环蛋白结合相结合，以鉴定阶段特异性直接Wnt靶基因。我们提出了一种连贯的前馈调节，涉及两类不同的直接母体Wnt靶基因，它们在β-连环蛋白结合的表达和持续性方面都有所不同。我们发现基因组β-连环蛋白结合与Foxh1相关的调控序列重叠，并证明直接母体Wnt靶基因表达需要Foxh1功能和Nodal/Tgfβ信号传导。我们的结果支持了一种新的范式，即直接Wnt靶基因通过特定背景机制进行共同调控，这将为未来胚胎发育以及更广泛的干细胞介导的体内平衡和人类疾病研究提供信息。
