Ethanol exposure drives colon location specific cell composition changes in a normal colon crypt 3D organoid model.
Ethanol exposure drives colon location specific cell composition changes in a normal colon crypt 3D organoid model.
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DOI：
10.1038/s41598-020-80240-1
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发表时间：
2021-01-11
影响因子：
4.6
通讯作者：
Casey G
中科院分区：
文献类型：
--
作者：
Devall M;Plummer SJ;Bryant J;Jennelle LT;Eaton S;Dampier CH;Huyghe JR;Peters U;Powell SM;Casey G
酒精一直被认为是结肠癌的危险因素。然而，其对正常结肠隐窝细胞作用的分子机制仍然知之甚少。我们使用核糖核酸测序来评估来自健康结肠(n = 34)的3D器官系对乙醇暴露(0.2%VOL：VOL)的转录反应。配对回归分析确定了2,162个差异表达基因对乙醇的反应。当按结肠位置分层时，在来自左结肠和右结肠的器官中发现了更多的差异表达基因，其中许多对应于细胞类型的特定标记。为了验证乙醇处理对结肠类器官种群的影响部分是由于细胞组成不同的假设，我们结合了来自正常结肠活检组织的外部单细胞RNA测序数据，以估计单细胞去卷积后的细胞比例。我们推断了细胞类型的变化，并观察到乙醇暴露后运输放大细胞的增加，左侧的器官类细胞比右侧的更多，伴随而来的是分化程度更高的细胞的减少。如果这发生在饮酒后的结肠，这将导致下层隐窝中细胞区的增加，那里的细胞分裂条件最佳，并有可能发生突变。
Alcohol is a consistently identified risk factor for colon cancer. However, the molecular mechanism underlying its effect on normal colon crypt cells remains poorly understood. We employed RNA-sequencing to asses transcriptomic response to ethanol exposure (0.2% vol:vol) in 3D organoid lines derived from healthy colon (n = 34). Paired regression analysis identified 2,162 differentially expressed genes in response to ethanol. When stratified by colon location, a far greater number of differentially expressed genes were identified in organoids derived from the left versus right colon, many of which corresponded to cell-type specific markers. To test the hypothesis that the effects of ethanol treatment on colon organoid populations were in part due to differential cell composition, we incorporated external single cell RNA-sequencing data from normal colon biopsies to estimate cellular proportions following single cell deconvolution. We inferred cell-type-specific changes, and observed an increase in transit amplifying cells following ethanol exposure that was greater in organoids from the left than right colon, with a concomitant decrease in more differentiated cells. If this occurs in the colon following alcohol consumption, this would lead to an increased zone of cells in the lower crypt where conditions are optimal for cell division and the potential to develop mutations.
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
30.8
作者：
Dunlop MG;Dobbins SE;Farrington SM;Jones AM;Palles C;Whiffin N;Tenesa A;Spain S;Broderick P;Ooi LY;Domingo E;Smillie C;Henrion M;Frampton M;Martin L;Grimes G;Gorman M;Semple C;Ma YP;Barclay E;Prendergast J;Cazier JB;Olver B;Penegar S;Lubbe S;Chander I;Carvajal-Carmona LG;Ballereau S;Lloyd A;Vijayakrishnan J;Zgaga L;Rudan I;Theodoratou E;Colorectal Tumour Gene Identification (CORGI) Consortium;Starr JM;Deary I;Kirac I;Kovacević D;Aaltonen LA;Renkonen-Sinisalo L;Mecklin JP;Matsuda K;Nakamura Y;Okada Y;Gallinger S;Duggan DJ;Conti D;Newcomb P;Hopper J;Jenkins MA;Schumacher F;Casey G;Easton D;Shah M;Pharoah P;Lindblom A;Liu T;Swedish Low-Risk Colorectal Cancer Study Group;Smith CG;West H;Cheadle JP;COIN Collaborative Group;Midgley R;Kerr DJ;Campbell H;Tomlinson IP;Houlston RS
通讯作者：
Houlston RS
影响因子：
30.8
作者：
Huyghe, Jeroen R.;Bien, Stephanie A.;Peters, Ulrike
通讯作者：
Peters, Ulrike
影响因子：
16.6
作者：
Donovan, Margaret K. R.;D'Antonio-Chronowska, Agnieszka;Frazer, Kelly A.
通讯作者：
Frazer, Kelly A.
影响因子：
8.4
作者：
Akhter, Munira;Kuriyama, Shinichi;Tsuji, Ichiro
通讯作者：
Tsuji, Ichiro