A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
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由 PBX1/2 指导的时空受限基因调控网络通过 HAND2 获得肢体模式特异性
DOI：
10.1101/2022.03.08.483529
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Losa M
中科院分区：
文献类型：
--
作者：
Losa M
发育生物学中一个悬而未决的问题集中在广泛分布于脊椎动物胚胎中的转录因子如何发挥组织特异性功能。本文以小鼠后肢为模型，研究了PBX TALE同源蛋白（主要被视为HOX辅助因子）在胚胎中普遍存在的情况下获得特定环境发育作用的难以捉摸的机制。我们首先证明了PBX1/2或转录调节因子HAND2的间质特异性缺失会产生相似的肢体表型。通过将组织特异性和暂时控制的突变与多组学方法相结合，我们在生物体水平上重建了一个基因调控网络（GRN），该网络由PBX1/2和HAND2在后肢间质细胞亚群中的相互作用共同指导。对多个胚胎组织中PBX1结合的全基因组分析进一步揭示了HAND2与PBX1结合区域亚群相互作用以调节肢体特异性grn。我们的研究阐明了混杂转录因子与显示域限制定位的辅因子合作指导组织特异性发育程序的基本原理。
A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs.
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