Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions
Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions
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DOI：
10.1073/pnas.2104832118
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发表时间：
2021-10
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通讯作者：
Vinod K. Mony;Anna Drangowska-Way;R. Albert;E. Harrison;Abbas Ghaddar;M. Horak;Wenfan Ke;Eyleen J. O’Rourke
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作者：
Vinod K. Mony;Anna Drangowska-Way;R. Albert;E. Harrison;Abbas Ghaddar;M. Horak;Wenfan Ke;Eyleen J. O’Rourke
基因通常编码具有特殊功能的蛋白质（如脂肪酶）。然而，该蛋白的功能，以及由此产生的基因，可能对不同环境下（例如，禁食和氧化应激）的存活至关重要。因此，常见的生存基因是如何在多种情况下被激活的？基于遗传学和数学模型，我们描述了两种转录激活模式：1)趋同-单一转录调控因子在多种环境下激活生存基因；2)情境-转录调控因子网络成员的活性/相互作用被微调，通过特定于环境的分子路径激活生存基因。研究结果强调了跨上下文分子推断的局限性，并提出了一种生物恢复力的经济策略。多细胞生物的可塑性涉及信号通路将环境（自然环境挑战或实验室扰动）转化为基因表达的特定环境变化。与此同时，信号分子与调节这些反应的转录因子（TF）之间的相互作用也具有上下文特异性。然而，当一个靶基因在不同的环境中做出反应时，在一种环境中发现的上游TF通常被推断为在不同的环境中调节它。因此，需要将这些稳定的tf靶基因对推断与环境特异性的稳态反应相协调。秀丽隐杆线虫基因lipl-3和lipl-4的诱导在许多遗传环境中被观察到，并且是禁食期间生存所必需的。我们发现DAF-16/FOXO在所有测试环境中介导lip -4诱导；因此，lipl-4调控似乎与上下文无关，并与跨上下文推断兼容。相反，daf -16介导的lipl-3的调节是特定环境的。DAF-16在禁食期间减少了lipl-3的诱导，但在氧化应激期间却促进了它的产生。通过离散动态建模和遗传上位，我们确定DAF-16在禁食期间抑制HLH-30/ tfeb -激活lipl-3的主要TF。相反，DAF-16在氧化应激时激活应激响应TF HSF-1，通过诱导lip -3促进秀丽隐杆线虫的存活。此外，在氧化应激期间，TF MXL-3以牺牲HLH-30为代价，促进HSF-1的优势地位，但在禁食期间则不然。这项研究显示了分子网络中功能相互作用的上下文特异性转移如何使细胞能够用有限数量的分子参与者特异性地响应大量的上下文，我们将这种转录调节模式称为“上下文化转录”。
Significance Genes often encode for proteins with specialized functions (e.g., lipase). However, the function of the protein, and hence the gene, may be critical for survival in diverse contexts (e.g., fasting and oxidative stress). Hence, how are common survival genes activated in multiple contexts? Based on genetics and mathematical modeling, we describe two modes of transcriptional activation: 1) convergent—a single transcriptional regulator activates the survival gene in multiple contexts—and 2) contextual—the activity/interaction of members of a network of transcriptional regulators is fine-tuned to activate the survival gene through molecular paths that are specific to a context. The results underscore the limitations of across-context molecular inferences and suggest an economic tactic to biological resilience. Plasticity in multicellular organisms involves signaling pathways converting contexts—either natural environmental challenges or laboratory perturbations—into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) regulating these responses are also context specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Reconciling these stable TF–target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16–mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB—the main TF activating lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3. Furthermore, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name “contextualized transcription.”