Foxf1-Wnt-Nr2f1级联促进斑马鱼心房心肌细胞分化

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
Ugo Coppola, Bitan Saha, Jennifer Kenney, Joshua S Waxman
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引用次数: 0

摘要

Nr2f 转录因子(TF)是脊椎动物心房心肌细胞(AC)分化的保守调节因子。然而,人们对 Nr2f 在 AC 中的表达机制知之甚少。在这里,我们发现了一个位于 nr2f1a 基因座 3' 的保守增强子,我们称之为 3'reg1-nr2f1a(3'reg1),它能促进 Nr2f1a 在 ACs 中的表达。对该增强子的序列分析发现了推定的 Lef/Tcf 和 Foxf TF 结合位点。3'reg1报告基因中Lef/Tcf位点的突变、Tcf7l1a的敲除以及对典型Wnt信号的操作都支持Tcf7l1a通过Wnt信号被去抑制,从而激活转基因增强子并促进AC分化。同样,3'reg1报告基因中的Foxf结合位点突变以及功能增益和功能缺失分析也支持Foxf1促进增强子的表达和AC分化。在功能上,我们发现 Wnt 信号作用于 Foxf1 的下游,促进 3'reg1 报告基因在 ACs 中的表达,而且重要的是,Foxf1 和 Wnt 信号作用都需要 Nr2f1a 来促进分化 ACs 的过剩。CRISPR 介导的内源性 3'reg1 缺失会削弱 Foxf1 和 Wnt 信号在斑马鱼胚胎中产生过剩 AC 的能力。总之,我们的数据支持涉及 Wnt 信号和 Foxf1 的保守调控网络的下游成员在 nr2f1a 增强子上发挥作用,促进斑马鱼心脏中 AC 的分化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish.

Nr2f transcription factors (TFs) are conserved regulators of vertebrate atrial cardiomyocyte (AC) differentiation. However, little is known about the mechanisms directing Nr2f expression in ACs. Here, we identified a conserved enhancer 3' to the nr2f1a locus, which we call 3'reg1-nr2f1a (3'reg1), that can promote Nr2f1a expression in ACs. Sequence analysis of the enhancer identified putative Lef/Tcf and Foxf TF binding sites. Mutation of the Lef/Tcf sites within the 3'reg1 reporter, knockdown of Tcf7l1a, and manipulation of canonical Wnt signaling support that Tcf7l1a is derepressed via Wnt signaling to activate the transgenic enhancer and promote AC differentiation. Similarly, mutation of the Foxf binding sites in the 3'reg1 reporter, coupled with gain- and loss-of-function analysis supported that Foxf1 promotes expression of the enhancer and AC differentiation. Functionally, we find that Wnt signaling acts downstream of Foxf1 to promote expression of the 3'reg1 reporter within ACs and, importantly, both Foxf1 and Wnt signaling require Nr2f1a to promote a surplus of differentiated ACs. CRISPR-mediated deletion of the endogenous 3'reg1 abrogates the ability of Foxf1 and Wnt signaling to produce surplus ACs in zebrafish embryos. Together, our data support that downstream members of a conserved regulatory network involving Wnt signaling and Foxf1 function on a nr2f1a enhancer to promote AC differentiation in the zebrafish heart.

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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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