Functional genomics analysis of human colon organoids identifies key transcription factors.
Functional genomics analysis of human colon organoids identifies key transcription factors.
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人类结肠类器官的功能基因组学分析确定了关键转录因子。
DOI：
10.1152/physiolgenomics.00113.2019
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发表时间：
2020
影响因子：
4.6
通讯作者：
Harris,Ann
中科院分区：
文献类型：
--
作者：
Yin,Shiyi;Ray,Greeshma;Kerschner,JennyL;Hao,Shuyu;Perez,Aura;Drumm,MitchellL;Browne,JamesA;Leir,Shih-Hsing;Longworth,Michelle;Harris,Ann
类器官是一种有价值的三维 (3D) 模型，可用于研究人类肠上皮的分化功能。它们是测量健康和疾病中上皮运输过程的特别强大的工具。尽管类器官肿胀和管腔内 pH 测量等生物测定方法已十分成熟，但其潜在的功能基因组学尚未得到很好的表征。在这里，我们将 ATAC-Seq 对开放染色质的全基因组分析与 RNA-Seq 的转录组作图相结合，以定义人类肠道类器官 (HIO) 的基因组特征。这些数据为研究肠上皮的关键生理和生化过程提供了重要工具。接下来，我们将 HIO 的转录组和开放染色质谱与 Caco2 结直肠癌系的等效数据集进行了比较，Caco2 结直肠癌系是肠上皮的重要二维 (2D) 模型。我们的结果定义了 HIO 和 Caco2 肠上皮的共同特征，并进一步说明了细胞系的癌症相关程序。 Caco2 包囊的产生使得能够询问 2D 和 3D 培养物的分子差异。对开放染色质峰的过度表达基序分析将尾部型同源框 2 (CDX2) 确定为 HIO 中的关键激活转录因子，但在 Caco2 的单层培养物中则不然。然而，CDX2 基序在 Caco2 囊肿的开放染色质中出现过多，增强了该因子在肠上皮分化和功能中的重要性。 HIO 和 Caco2 转录组的交叉进一步显示离子运输和紧密连接完整性等途径的功能重叠。这些数据有助于了解人类肠道类器官生物学。
Organoids are a valuable three-dimensional (3D) model to study the differentiated functions of the human intestinal epithelium. They are a particularly powerful tool to measure epithelial transport processes in health and disease. Though biological assays such as organoid swelling and intraluminal pH measurements are well established, their underlying functional genomics are not well characterized. Here we combine genome-wide analysis of open chromatin by ATAC-Seq with transcriptome mapping by RNA-Seq to define the genomic signature of human intestinal organoids (HIOs). These data provide an important tool for investigating key physiological and biochemical processes in the intestinal epithelium. We next compared the transcriptome and open chromatin profiles of HIOs with equivalent data sets from the Caco2 colorectal carcinoma line, which is an important two-dimensional (2D) model of the intestinal epithelium. Our results define common features of the intestinal epithelium in HIO and Caco2 and further illustrate the cancer-associated program of the cell line. Generation of Caco2 cysts enabled interrogation of the molecular divergence of the 2D and 3D cultures. Overrepresented motif analysis of open chromatin peaks identified caudal type homeobox 2 (CDX2) as a key activating transcription factor in HIO, but not in monolayer cultures of Caco2. However, the CDX2 motif becomes overrepresented in open chromatin from Caco2 cysts, reinforcing the importance of this factor in intestinal epithelial differentiation and function. Intersection of the HIO and Caco2 transcriptomes further showed functional overlap in pathways of ion transport and tight junction integrity, among others. These data contribute to understanding human intestinal organoid biology.
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影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
肠类器官培养模型是研究 IBD 上皮屏障功能的有价值的系统
影响因子：
24.5
作者：
P. Xu;H. Becker;M. Elizalde;A. Masclee;D. Jonkers
通讯作者：
D. Jonkers
影响因子：
29.4
作者：
Zhao J;Bulek K;Gulen MF;Zepp JA;Karagkounis G;Martin BN;Zhou H;Yu M;Liu X;Huang E;Fox PL;Kalady MF;Markowitz SD;Li X
通讯作者：
Li X
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影响因子：
7.8
作者：
GUINEBAULT, C;PAYRASTRE, B;RACAUDSULTAN, C;MAZARGUIL, H;BRETON, M;MAUCO, G;PLANTAVID, M;CHAP, H
通讯作者：
CHAP, H
囊性纤维化肠类器官中通读剂对过早终止密码子的抑制有限。
影响因子：
5.2
作者：
D. D. Z. Ommen;Lodewijk A W Vijftigschild;E. Kruisselbrink;A. Vonk;J. Dekkers;H. Janssens;K. W. Groot;C. K. V. D. Ent;J. Beekman
通讯作者：
J. Beekman