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胃黏膜肠上皮化生的H3K27ac增强子重编程特征及转录调控机制
Reprogramming characteristics of H3K27ac-marked enhancer in gastric intestinal metaplasia and its transcriptional regulatory mechanism
- 陆军军医大学学报 2023年45卷第6期 页码：500-509
- 作者机构：
400042 重庆，陆军特色医学中心消化内科，消化系统肿瘤精准防治重庆市重点实验室
- 作者简介：
[王涛，E-mail: 269839470@163.com WANG Tao, E-mail: 269839470@163.com
[王斌，E-mail: wb_tmmu@126.com WANG Bin, E-mail: wb_tmmu@126.com
- 基金信息：国家自然科学基金优秀青年科学项目(81822032);重庆市自然科学基金杰出青年项目(CSTC2019JCYJJQX0027)
DOI：10.16016/j.2097-0927.202210071
中图分类号： R394-33;R394.3;R735.2收稿：2022-10-11，
修回：2023-01-28，
纸质出版：2023-03-30
- 稿件说明：
移动端阅览
刘文康, 吴林育, 喻博, 等. 胃黏膜肠上皮化生的H3K27ac增强子重编程特征及转录调控机制[J]. 陆军军医大学学报, 2023,45(6):500-509.
Wenkang LIU, Linyu WU, Bo YU, et al. Reprogramming characteristics of H3K27ac-marked enhancer in gastric intestinal metaplasia and its transcriptional regulatory mechanism[J]. Journal of Army Medical University, 2023, 45(6): 500-509.
刘文康, 吴林育, 喻博, 等. 胃黏膜肠上皮化生的H3K27ac增强子重编程特征及转录调控机制[J]. 陆军军医大学学报, 2023,45(6):500-509. DOI： 10.16016/j.2097-0927.202210071.
Wenkang LIU, Linyu WU, Bo YU, et al. Reprogramming characteristics of H3K27ac-marked enhancer in gastric intestinal metaplasia and its transcriptional regulatory mechanism[J]. Journal of Army Medical University, 2023, 45(6): 500-509. DOI： 10.16016/j.2097-0927.202210071.
摘要
目的
2
描绘胃黏膜肠上皮化生(intestinal metaplasia
IM)(肠化)组织增强子标志H3K27ac修饰的全基因组分布图谱，探讨增强子调控肠化的作用机制。
方法
2
于本院收集41例肠化胃黏膜与21例正常胃黏膜进行H3K27ac染色质靶向切割和标签化(Cleavage Under Targets and Tagmentation
CUT&Tag)测序与RNA测序，比较两种组织的H3K27ac修饰数量、信号强度差异，分析增强子重编程特征；探讨增强子相关转录因子调控肠化基因表达的分子机制。
结果
2
相比正常胃黏膜，肠化组织的H3K27ac修饰数量、信号强度均显著增加，其重编程区域主要位于增强子；在肠化组织的高变异增强子基因座中，活性升高的增强子占92.4%，后者可能上调大量肠上皮细胞相关基因表达，改变肠化细胞表型和生物学特性；肠化增强子区域富集了CDX2等14个转录因子的结合基序，它们在肠化组织表达上调，组成转录因子调控网络，可能在增强子激活肠化相关基因表达中发挥重要作用。
结论
2
本研究采用表观组、转录组测序及整合分析，发现全基因组增强子重塑是肠化的一个重要表观修饰特征，增强子可能通过招募CDX2等转录因子形成调控网络，协同上调肠化相关基因表达。
Abstract
Objective
2
To profile the genome-wide distribution of H3K27ac-marked enhancers in gastric intestinal metaplasia (IM) tissues and to investigate the potential regulatory mechanism of enhancers on IM.
Methods
2
IM tissues from 41 patients and normal gastric mucosa from 21 healthy individuals were collected for analysis using Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing and RNA sequencing. The number and signal intensity of H3K27ac modifications in the 2 tissues were compared to reveal the reprogramming characteristics of the enhancers in the IM tissues. Meanwhile
the underlying regulatory mechanism of enhancer-associated transcription factors on the expression of IM-related genes were investigated.
Results
2
As compared with normal gastric mucosa
the number and signal intensity of H3K27ac modifications were significantly elevated in the IM tissues
and the reprogramming areas were mainly located in the enhancers. The enhancers with greatly increased activity accounted for 92.4% of all variant enhancer loci in IM
which improved the expression of many intestinal epithelium-related genes
leading to altered phenotypes and biological properties of metaplastic mucous cells. The binding motifs of 14 transcription factors including CDX2 were identified by enrichment analysis in the enhancer loci. These transcription factors were up-regulated in the IM tissues and thus constituted a transcriptional regulatory network
and may play an important role in enhancer activating IM-related genes.
Conclusion
2
Through integration analysis of epigenetic and transcriptomic sequencing
enhancer reprogramming is identified as a critical epigenetic modification feature in gastric IM. Multiple transcription factors like CDX2 might be recruited to the enhancer loci
and then generate a regulatory network to synergistically up-regulate the expression of IM-related genes.
关键词
Keywords
references
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