Preparing macrophages for the future

doi:10.1126/science.abj2040

GSTDTAP > 气候变化

DOI	10.1126/science.abj2040
	Preparing macrophages for the future
	Nagarajan Nandagopal; Ashwini Jambhekar; Galit Lahav
	2021-06-18
发表期刊	Science
出版年	2021
英文摘要	Cells live in complex environments and must respond appropriately to extracellular signals. Such responses often involve regulating the expression of hundreds of genes through transcription factors (TFs). Many TFs are activated by multiple signals and regulate the expression of distinct genes in response to each. How extracellular information is “encoded” in TF activity and subsequently “decoded” to orchestrate gene expression is a fundamental question in biology. Intriguingly, some TFs such as nuclear factor κB (NF-κB) and p53 encode signaling information in their temporal dynamics ([ 1 ][1]). Studies have shown that signaling dynamics can be used to control the induced expression levels ([ 2 ][2]), types ([ 3 ][3]), or ratios ([ 4 ][4]) of genes. On page 1349 of this issue, Cheng et al. ([ 5 ][5]) report a previously unknown role for TF dynamics: They show that NF-κB dynamics not only control how genes respond in the present but also reconfigure the cell to control gene expression in response to future stimulation. In macrophages, which act as sentinel cells of the innate immune system, NF-κB dynamics was shown to encode signal identity. For example, activation by toxins released from invading bacteria leads to sustained NF-κB activity, whereas activation by inflammatory signals from other immune cells leads to oscillations in NF-κB activity ([ 6 ][6], [ 7 ][7]). Rather than focusing directly on which genes' expression are induced by NF-κB, and by how much, Cheng et al. analyzed the NF-κB “epigenome,” a set of factors that influences the potential for expression of genes to be induced upon TF activation. ![Figure][8] Signal-specific nuclear factor κB dynamics In macrophages, the transcription factor nuclear factor κB (NF-κB) can be activated either with oscillatory or sustained temporal dynamics, depending on the signal. Under oscillatory dynamics, inactive enhancers remain nucleosome-bound. By contrast, sustained dynamics can remodel enhancers through nucleosome displacement and histone 3 Lys4 (H3K4) methylation. After a second exposure to the same signal, enhancers that were activated by sustained NF-κB dynamics induce expression of their associated genes, whereas these genes remain inactive under oscillatory dynamics. GRAPHIC: K. FRANKLIN/ SCIENCE The status of “enhancers,” DNA sequences bound by TFs to control gene expression, is a particularly important aspect of the epigenome. In some cases, enhancers are bound by nucleosomes, which obstruct TF binding. Such enhancers cannot activate genes until the nucleosomes are displaced. Other enhancers are readily available for TFs to bind and facilitate gene expression and are considered to be active. The set of genes whose expression can be induced and their expression levels depend on how these two classes of enhancers are distributed in the genome. This layer of regulation provides a means for different cell types to regulate different sets of genes by using the same TFs. It also enables a cell to change its response to the same signal and thus adapt to the environment. Cheng et al. investigated the status of NF-κB–bound enhancers in macrophages derived from mice after stimulating the cells with signals previously shown to activate NF-κB with different dynamics. They found that signals that led to sustained NF-κB activity increased the number of active enhancers compared with signals that produced oscillatory activity. To directly test whether this difference was due to NF-κB dynamics, the authors blocked normal oscillations by disengaging a well-characterized negative-feedback loop in the NF-κB pathway, which did not alter other features of the response such as activation intensity. Removing NF-κB oscillations in this manner increased the number of active NF-κB–dependent enhancers. Thus, although both oscillatory and non-oscillatory NF-κB dynamics induce gene expression through already active enhancers, non-oscillatory activation also reconfigures the epigenome by activating additional enhancers. What effect does this have on the cell? Because the epigenome defines the set of genes whose expression can be induced by NF-κB, one scenario is that by increasing the number of active enhancers, nonoscillatory NF-κB dynamics change the set of genes that could respond to future stimulation of the pathway. Indeed, analysis of gene expression after a second phase of sustained NF-κB activation showed induction of hundreds of genes not induced upon repeat stimulation of oscillatory NF-κB (see the figure). Thus, it appears that the functions of NF-κB as an inducer of gene expression and as a modifier of the epigenome (likely in conjunction with other proteins) are separable according to its temporal dynamics. On the basis of modeling, the authors suggest that this separation is achieved through the many steps involved in unwrapping inactive enhancers from nucleosomes, which demands persistent nuclear NF-κB—that is, non-oscillatory dynamics. Modifying the epigenome provides NF-κB with the ability to record its activation and affect future cellular responses. Other forms of this phenomenon, broadly called epigenetic transcriptional memory, have been described ([ 8 ][9]), including in macrophages ([ 9 ][10]). It will be interesting to compare enhancer activation by NF-κB to other mechanisms of transcriptional memory, in terms of stability, fidelity, and lifetime. At a mechanistic level, it remains to be determined how NF-κB activity duration translates to nucleosome displacement and how the proposed multistep reaction mechanism compares with classic kinetic proofreading ([ 10 ][11]) or circuit-based mechanisms for duration sensing ([ 11 ][12]). The responses of target genes to other TFs are sensitive to oscillation frequency and duration ([ 12 ][13]); the relevance of the proposed mechanism to these pathways will be worth investigating. At the level of the cellular response, the functional consequences of organizing NF-κB target genes into multiple cohorts are currently unclear. Does it lead to macrophage adaptation to particular immune threats, as suggested previously ([ 9 ][10], [ 13 ][14])? Maybe this response can be “tuned” by changing the duration or intensity of the initial stimulus. The discovery by Cheng et al. thus opens up several new lines of inquiry that will help to better understand how NF-κB orchestrates specific responses to different stimuli. More generally, other oscillatory TFs have known roles in regulating the epigenome ([ 14 ][15], [ 15 ][16]). It will be fascinating to see whether similar principles apply to decoding dynamics and controlling the activation of target genes in other systems. 1. [↵][17]1. J. E. Purvis, 2. G. Lahav , Cell. 152, 945 (2013). [OpenUrl][18][CrossRef][19][PubMed][20][Web of Science][21] 2. [↵][22]1. K. Lane et al ., Cell Syst. 4, 458 (2017). [OpenUrl][23] 3. [↵][24]1. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/330800
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Nagarajan Nandagopal,Ashwini Jambhekar,Galit Lahav. Preparing macrophages for the future[J]. Science,2021.
APA	Nagarajan Nandagopal,Ashwini Jambhekar,&Galit Lahav.(2021).Preparing macrophages for the future.Science.
MLA	Nagarajan Nandagopal,et al."Preparing macrophages for the future".Science (2021).