Ileal Transcriptomic Analysis in Paediatric Crohn's Disease Reveals IL17- and NOD-signalling Expression Signatures in Treatment-naïve Patients and Identifies Epithelial Cells Driving Differentially Expressed Genes.
Ileal Transcriptomic Analysis in Paediatric Crohn's Disease Reveals IL17- and NOD-signalling Expression Signatures in Treatment-naïve Patients and Identifies Epithelial Cells Driving Differentially Expressed Genes.
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DOI：
10.1093/ecco-jcc/jjaa236
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发表时间：
2021-05-04
期刊：
影响因子：
--
通讯作者：
Ennis S
中科院分区：
文献类型：
--
作者：
Ashton JJ;Boukas K;Davies J;Stafford IS;Vallejo AF;Haggarty R;Coelho TAF;Batra A;Afzal NA;Vadgama B;Williams AP;Beattie RM;Polak ME;Ennis S
克罗恩病[CD]通过宿主-环境相互作用而产生。异常基因表达是由干扰的途径激活或对细菌的反应引起的。我们的目的是确定儿童CD的激活途径和驱动细胞类型。我们采用了当代靶向自身免疫RNA测序，平行于单细胞测序，回肠组织来源于儿科CD和对照。进行加权基因共表达网络分析[WGCNA]并确定差异表达基因[DEG]。我们整合临床数据，以确定与结果相关的共表达模块。总共纳入了27例初治CD [TN-CD]、26例确诊CD患者和17例对照。WGCNA揭示了TN-CD患者的31个基因特征，但没有建立CD，也没有控制。CSF 3R基因是该模块中的枢纽，并且在中性粒细胞扩增和分化中是关键的。与对照组[分别为p = 2.61 x 10-15和p = 9.13 x 10-14]和已建立的CD [均为p = 0.0055]相比，TN CD中的抗菌基因（包括S100 A12和钙卫蛋白亚基S100 A9）显著上调。基因富集分析证实了TN-CD患者中IL 17-、NOD-和Oncostatin-M-信号通路的上调，这在WGCNA和DEG分析中都得到了鉴定。一个上调的基因签名被富集为促进Th 17细胞分化的转录本，并与复发时间延长相关[相关系数-0.36，p = 0.07]。TN-CD患者的单细胞测序鉴定了驱动S100 A9差异表达的特化上皮细胞。通过单细胞基因表达确定的细胞组证明了单核细胞和上皮细胞中IL 17信号传导的富集。来自未接受过治疗的儿科患者的回肠组织中驱动IL 17-、NOD-和抑瘤素-M-信号传导的基因显著上调。该信号由表达抗微生物基因转录物的上皮细胞的不同子集驱动。
Crohn’s disease [CD] arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD. We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted gene co-expression network analysis [WGCNA] was performed and differentially expressed genes [DEGs] were determined. We integrated clinical data to determine co-expression modules associated with outcomes. In all, 27 treatment-naive CD [TN-CD], 26 established CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established CD, nor controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes, including S100A12 and the calprotectin subunit S100A9, were significantly upregulated in TN CD compared with controls [p = 2.61 x 10-15 and p = 9.13 x 10-14, respectively] and established CD [both p = 0.0055]. Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse [correlation-coefficient-0.36, p = 0.07]. Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells. Ileal tissue from treatment-naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
29.4
作者：
Howell KJ;Kraiczy J;Nayak KM;Gasparetto M;Ross A;Lee C;Mak TN;Koo BK;Kumar N;Lawley T;Sinha A;Rosenstiel P;Heuschkel R;Stegle O;Zilbauer M
通讯作者：
Zilbauer M
影响因子：
4.4
作者：
Lee, Jimmy W.;Wang, Ping;Straus, Daniel S.
通讯作者：
Straus, Daniel S.
影响因子：
29.4
作者：
Kotlarz, Daniel;Beier, Rita;Klein, Christoph
通讯作者：
Klein, Christoph