A draft network of ligand–receptor-mediated multicellular signalling in human

題目：人體內(nèi)配體?受體介導的多細胞信號網(wǎng)絡(luò)草圖

作者及單位：

JordanA. Ramilowski, Tatyana Goldberg, Jayson Harshbarger, Edda Kloppmann, Marina Lizio, Venkata P. Satagopam, Masayoshi Itoh, Hideya Kawaji, Piero Carninci, Burkhard Rost&AlistairR. R. Forrest

Alistair R. R. Forrest

• RIKEN Center for Life Science Technologies, Division of Genomic Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045 Japan
• Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, PO Box 7214, 6 Verdun Street, Nedlands, Perth, Western Australia 6008, Australia

發(fā)表刊物及時間：

Nature Communications volume 6, Article number: 7866 (2015) Published: 22 July 2015

摘要：

Cell-to-cell communication across multiple cell types and tissues strictly governs proper functioning of metazoans and extensively relies on interactions between secreted ligands and cell-surface receptors. Herein, we present the first large-scale map of cell-to-cell communication between 144 human ==primary cell==（原代細胞） types. We reveal that most cells express tens to hundreds of ligands and receptors to create a highly connected signalling network through multiple ligand–receptor paths. We also observe extensive autocrine signalling with approximately two-thirds of partners possibly interacting on the same cell type. We find that plasma membrane and secreted proteins have the highest cell-type specificity, they are evolutionarily younger than intracellular proteins, and that most receptors had evolved before their ligands. We provide an online tool to interactively query and visualize our networks and demonstrate how this tool can reveal novel cell-to-cell interactions with the prediction that mast cells signal to monoblastic lineages via the CSF1–CSF1R interacting pair.

多種細胞類型和組織之間的細胞?細胞通訊嚴格控制著后生動物的正常功能，并廣泛地依賴于分泌配體和細胞表 面受體之間的相互作用。在此叔收，我們率先提出了144種人類原代細胞類型當中的大規(guī)模細胞?細胞間通訊圖譜蹂风。 我們揭示了大部分表達數(shù)十至數(shù)百個配體和受體的細胞會通過多種配體?受體通路產(chǎn)生高度連接的信號傳導網(wǎng) 絡(luò)。同時渡讼，我們也觀察到廣泛的自分泌信號傳導，大約2/3的伴侶可能跟同種細胞類型互作。我們發(fā)現(xiàn)質(zhì)膜和 分泌蛋白有著最高的細胞類型特異性其做，他們在進化上比胞內(nèi)蛋白更年輕顶考，并且大多數(shù)受體比它們的配體先形 成。我們提供了一個在線工具妖泄，用于交互式查詢和可視化我們的網(wǎng)絡(luò)驹沿，并演示該工具如何通過CSF1?CSF1R相 互作用對來預測肥大細胞對單核細胞譜系信號傳導，從而揭示新的細胞間相互作用

圖表選析：

image.png

Figure 1: Relationship between protein subcellular localization, cell-type specificity and gene ages. 蛋白亞細胞定位蹈胡、 細胞類型特異性 和基因年齡間的聯(lián)系

(a) Breakdown of known subcellular localization of protein-coding genes expressed > 1 TPM in at least one primary state for which protein ages were available. （a）蛋白質(zhì)編碼基因的已知亞細胞定位的分解在至少一種可獲得蛋白質(zhì)年齡的原始狀態(tài)中表達> 1TPM渊季。

(b) Interquartile range distributions (whisker boxes) and relative cell-type specificity for each protein subcellular compartment from FANTOM5 primary cell expression profiles. Both secreted and plasma membrane proteins are significantly more cell-type specific than nuclear and cytoplasmic proteins (each Mann – Whitney U-test-adjusted ==P value<000.1==（此處應該是標錯了？）). （b） 來自 FANTOM5 原代細胞表達譜的每個蛋白質(zhì)亞 細胞區(qū)室的四分位數(shù)范圍分布（箱型圖） 和相對細胞類型特異性罚渐。 分 泌蛋白和質(zhì)膜蛋白都比核蛋白和細胞質(zhì)蛋白明顯更具細胞類型特異 性（每個 Mann-Whitney U-檢驗調(diào)整后 P 值都小于 000.1） 却汉。

(c) Relative fractions of proteins at each evolutionary stage for selected subcellular localization (secreted, plasma membrane, nucleus, cytoplasmic and other) using the methods of Wagner. All fractions at a given age add to 100%. （c） 使用 Wagner 的方法， 在選擇的亞細胞定 位（分泌的荷并， 質(zhì)膜合砂， 細胞核， 細胞質(zhì)和其他） 的每個進化階段的蛋白 質(zhì)的相對分數(shù)源织。 給定年齡的所有片段均增加至 100％翩伪。

(d) As in c but scaled for visualization purposes to the number of nuclear proteins. Both secreted (average age: 412.2mya) and plasma membrane (average age: 517.2mya) proteins are significantly younger than nuclear (average age: 663.1mya) and cytoplasmic proteins (average age: 855.1mya), each Mann–Whitney U-test-adjusted P value<000.1. Note: exact numbers of proteins for each subcellular localization class in each phylostrata are available in Supplementary Data 1. 如圖 c， 但為了可視化而縮放了核蛋白的數(shù)量谈息。 分泌蛋白（平均年 齡： 412.2mya（million of years ago））和質(zhì)膜蛋白（平均年齡： 517.2mya） 明顯比核蛋白（平均年齡： 663.1mya） 和細胞質(zhì)蛋白質(zhì)（平均年齡： 855.1mya） 更年輕缘屹， 每個 Mann-Whitney U-檢驗 -adjusted P value 小 于 000.1。 注意： 附錄數(shù)據(jù) 1 中提供了任一層級中每個亞細胞定位類 別的確切蛋白質(zhì)數(shù)量黎茎。

image.png

Figure 2: Comparative age of genes encoding receptors and ligands.

圖2：編碼受體和配體的基因的年齡比較

Top and left panels list the number of ligands and receptors estimated to have arisen at each phylostratum using the method of Wagner21. Middle panel shows the number of ligand–receptor pairs observed in a given phylostrata. Intensity of red scales with the number of pairs. Note: many interactions (297 pairs) appeared at the same evolutionary stage (diagonal boxes), but we also observe a significant enrichment for 1,081 pairs where the receptor had appeared before the ligand as compared with 431 pairs, where the ligand had appeared first (binomial one-sided P value<0.001; 95% confidence interval [0.695, 1]).

上方和左方列出了使用Wagner21的方法估計在每個系統(tǒng)發(fā)育層級產(chǎn)生的配體和受體的數(shù)量囊颅。中間部分顯示了在給定的系統(tǒng)發(fā)育層級中觀察到的配體 - 受體對的數(shù)量。紅色強度與對數(shù)的比例傅瞻。注意：許多相互作用（297對）出現(xiàn)在相同的進化階段（對角線框）踢代，但我們也觀察到1,081對的顯著富集，其中受體出現(xiàn)在配體之前嗅骄，而431對胳挎，其中配體首先出現(xiàn)（二項式單側(cè)P值<0.001; 95％置信區(qū)間[0.695,1]。

Using our reference ligand–receptor pairs and the protein age estimates20,21, we examined whether the interacting partners appeared during the same evolutionary period as previously reported33, or if one had preceded the other29. We found that many cognate partners originated at the same phylostratum (273 pairs). However, we also observed an excess of 1,082 pairs where the ligand was younger than the receptor as compared with only 431 pairs where the ligand was older

利用我們的參 考配體-受體對和蛋白質(zhì)年齡估計值20溺森， 21慕爬，我們檢查了相互作用的伙伴是否出現(xiàn)在與先前報道的33相 同的進化時期，還是在另一個之前29屏积。我們發(fā)現(xiàn)許多同源伴侶起源于同一系統(tǒng)層(273對)医窿。然而，我們 也觀察到配體比受體年輕的超過1炊林， 082對姥卢，而在配體較老的情況下，只有431對。 (即大多數(shù)受體都是 在配體之前進化的)

image.png

Figure 4: Ligand–receptor signalling network interface (hive view).

The results of a search for the CSF1–CSF1R ligand–receptor pair, filtered for the top cell-to-cell paths (ranked by the product of CSF1 and CSF1R expression). In this network, stimulated mast cells express the highest levels of CSF1 (1,109 TPM), while CD14+ derived endothelial progenitor cells express the highest levels of CSF1R (699 TPM). Users can select cells and/or ligand–receptor (LR) pairs of interest and filter edges and nodes based on expression levels of L and R. The interface is available at: http://fantom.gsc.riken.jp/5/suppl/Ramilowski_et_al_2015/.

圖 4:配體受體信號網(wǎng)絡(luò)接口(hive 視圖) 搜索 CSF1 - CSF1R 配體-受體對的結(jié)果独榴，篩選頂級細胞到細胞的路徑(按 CSF1 和 CSF1R 表達的乘積排序)僧叉。在這個網(wǎng)絡(luò)中，受刺激的肥大細胞表達最高水平的 CSF1 (1109 TPM)棺榔，而 CD14+來源的內(nèi)皮祖細胞表達最高水平的 CSF1R (699 TPM)瓶堕。 用戶可以根據(jù) L 和 R 的表達水平選擇感興趣的細胞和/或配體受體(LR)對，并對邊緣和節(jié)點進行過濾症歇。 網(wǎng)址 是 http://fantom.gsc.riken.jp/5/suppl/Ramilowski_et_al_2015/

翻譯小組：

葉名琛郎笆、王俊豪、陳志榮当船、鄧峻瑋题画、鄭凌伶