Unexpected novel relational links uncovered by extensive developmental profiling of nuclear receptor expression.
Unexpected novel relational links uncovered by extensive developmental profiling of nuclear receptor expression.
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DOI：
10.1371/journal.pgen.0030188
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发表时间：
2007-11
期刊：
影响因子：
4.5
通讯作者：
Laudet V
中科院分区：
文献类型：
--
作者：
Bertrand S;Thisse B;Tavares R;Sachs L;Chaumot A;Bardet PL;Escrivà H;Duffraisse M;Marchand O;Safi R;Thisse C;Laudet V
核受体(NRs)是一类转录因子，参与胚胎发育、动态平衡和代谢性疾病等多种生物学过程。为了研究NRs在发育中的作用，了解单个基因在何时何地表达是至关重要的。虽然利用逆转录聚合酶链式反应和/或DNA微阵列在果蝇和小鼠等经典模型系统中进行了系统的表达研究，但还没有在全球范围内建立描述NR在胚胎发育过程中参与的系统图谱。本研究采用系统生物学方法，采用整体原位杂交技术，对斑马鱼发育过程中(101个基因)所有NR基因及其主要转录辅助调控因子的动态时空表达进行了系统分析。这个广泛的数据集建立了NRs和协同调节因子之间的重叠表达模式，表明了分层的转录网络。这一完整的发育概况提供了一种前所未有的对NRs在胚胎发育过程中表达的检查，揭示了它们在中枢神经系统和视网膜形成过程中的潜在功能。此外，我们的研究表明，激素作用的组织特异性更多地是由受体而不是它们的共同调节器赋予的。最后，对这一全球资源的进一步进化分析导致我们提出，重复基因的新功能发生在蛋白质序列和RNA表达模式的水平上。总之，NRs的这个表达数据库为深入研究每个NR个体的生物学功能以及研究它们在超家族中的组合调控电路提供了新的途径。NRs是控制后生动物发育、代谢和繁殖的关键分子。由于NRs与许多人类疾病有关，如癌症、代谢综合征和激素抵抗，它们是重要的药物靶点，正受到密切关注，以更好地了解它们的生物学功能。在本研究中，我们确定了所有NR基因及其主要转录辅调节因子在斑马鱼发育过程中的表达模式。我们使用斑马鱼是因为其胚胎的透明度使我们能够进行从早期发育到后期器官发生的整体原位杂交。这一完整的发育概况提供了一个前所未有的关于胚胎发育过程中NR表达的视角，揭示了它们在中枢神经系统和视网膜形成过程中的潜在功能。我们观察到，与NR基因相反，只有少数协同调节因子表现出限制性的表达模式，这表明激素作用的组织特异性更多地是由受体而不是它们的协同调节因子赋予的。最后，通过对重复基因表达模式差异的进化分析，我们观察到新的功能化发生在蛋白质序列和mRNA表达模式的水平上。综上所述，我们的数据为整个基因家族在发育过程中的功能分析提供了起点，并呼吁研究新陈代谢和发育之间的交叉。
Nuclear receptors (NRs) are transcription factors that are implicated in several biological processes such as embryonic development, homeostasis, and metabolic diseases. To study the role of NRs in development, it is critically important to know when and where individual genes are expressed. Although systematic expression studies using reverse transcriptase PCR and/or DNA microarrays have been performed in classical model systems such as Drosophila and mouse, no systematic atlas describing NR involvement during embryonic development on a global scale has been assembled. Adopting a systems biology approach, we conducted a systematic analysis of the dynamic spatiotemporal expression of all NR genes as well as their main transcriptional coregulators during zebrafish development (101 genes) using whole-mount in situ hybridization. This extensive dataset establishes overlapping expression patterns among NRs and coregulators, indicating hierarchical transcriptional networks. This complete developmental profiling provides an unprecedented examination of expression of NRs during embryogenesis, uncovering their potential function during central nervous system and retina formation. Moreover, our study reveals that tissue specificity of hormone action is conferred more by the receptors than by their coregulators. Finally, further evolutionary analyses of this global resource led us to propose that neofunctionalization of duplicated genes occurs at the levels of both protein sequence and RNA expression patterns. Altogether, this expression database of NRs provides novel routes for leading investigation into the biological function of each individual NR as well as for the study of their combinatorial regulatory circuitry within the superfamily. NRs are key molecules controlling development, metabolism, and reproduction in metazoans. Since NRs are implicated in many human diseases such as cancer, metabolic syndrome, and hormone resistance, they are important pharmaceutical targets and are under intense scrutiny to better understand their biological functions. In the present study, we determined the expression patterns of all NR genes as well as their main transcriptional coregulators during zebrafish development. We used zebrafish because the transparency of its embryo allows us to perform whole-mount in situ hybridization from early development to late organogenesis. This complete developmental profiling offers an unprecedented view of NR expression during embryogenesis, uncovering their potential function during central nervous system and retina formation. We observed that in contrast to NR genes, only a few coregulators exhibit a restricted expression pattern, suggesting that tissue specificity of hormone action is conferred more by the receptors than by their coregulators. Lastly, by evolutionary analysis of expression pattern divergence of duplicated genes, we observed that neofunctionalization occurs at the levels of both protein sequence and mRNA expression patterns. Taken together, our data provide the starting point for functional analysis of an entire gene family during development and call for the study of the intersection between metabolism and development.
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影响因子：
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作者：
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通讯作者：
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作者：
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