Remodeling characteristics of H3K27me3-marked silencers in gastric signet-ring cell carcinoma and its transcriptional regulatory function

DU Aibei; REN Yuanfeng; CHU Zhaole; LIU Biying; LI Xianfeng; XIANG Junyu; CHEN Dongfeng; WANG Tao; WANG Bin; GUO Haiying; ZHANG Xuan; LI Yuhong

doi:10.16016/j.2097-0927.202407095

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Remodeling characteristics of H3K27me3-marked silencers in gastric signet-ring cell carcinoma and its transcriptional regulatory function

Monographic Reports | 更新时间：2025-03-11

- Remodeling characteristics of H3K27me3-marked silencers in gastric signet-ring cell carcinoma and its transcriptional regulatory function
- Journal of Army Medical University Vol. 47, Issue 5, Pages: 417-425(2025)
- 作者机构：
  
  1.陆军军医大学基础医学院细胞生物学教研室，重庆
  2.陆军特色医学中心（第三军医大学大坪医院）消化内科，消化系统肿瘤精准防治重庆市重点实验室，重庆
  3.重庆市中医院肿瘤科，重庆
- 作者简介：
- 基金信息：
  
  the National Natural Science Foundation for Excellent Young Scientists of China(81822032);the General Project of Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0162)
- DOI：10.16016/j.2097-0927.202407095
  CLC： R394.3;R730.23;R735.2
- Received：23 July 2024，
  
  Revised：16 August 2024，
  
  Published：15 March 2025
- 稿件说明：
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杜艾贝，任原锋，储召乐，等.胃印戒细胞癌的H3K27me3沉默子重塑特征及转录调控功能［J］.陆军军医大学学报，2025，47（05）：417-425.DOI：10.16016/j.2097-0927.202407095.

DU A B，REN Y F，CHU Z L，et al.Remodeling characteristics of H3K27me3-marked silencers in gastric signet-ring cell carcinoma and its transcriptional regulatory function［J］.J Army Med Univ，2025，47（05）：417-425.DOI：10.16016/j.2097-0927.202407095.
杜艾贝，任原锋，储召乐，等.胃印戒细胞癌的H3K27me3沉默子重塑特征及转录调控功能［J］.陆军军医大学学报，2025，47（05）：417-425.DOI：10.16016/j.2097-0927.202407095. DOI：

DU A B，REN Y F，CHU Z L，et al.Remodeling characteristics of H3K27me3-marked silencers in gastric signet-ring cell carcinoma and its transcriptional regulatory function［J］.J Army Med Univ，2025，47（05）：417-425.DOI：10.16016/j.2097-0927.202407095. DOI：

摘要

目的

通过表观遗传组学技术，解析胃印戒细胞癌（signet-ring cell carcinoma of the stomach， SRCC）的H3K27me3沉默子的全基因组特征及其对基因转录的调控作用，以阐明SRCC恶性进展的表观调控机制。

方法

采集2021年1月至2023年12月陆军特色医学中心消化内科35例胃镜样本（正常胃窦/胃体15例，SRCC 20例）。采用以下多组学分析：染色质可及性测序（assay for transposase-accessible chromatin with high-throughput sequencing，ATAC-seq）检测染色质开放区域；染色质靶向捕获测序（cleavage under targets and tagmentat

ion，CUT

Tag）捕获H3K27me3沉默子区域；转录组测序（transcriptome sequencing，RNA-seq）分析转录组。测序于Illumina NovaSeq 6000平台完成（符合深度标准）。通过DESeq2筛选H3K27me3相关差异基因（|Log

FC|

1，FDR

0.05），并通过基因本体论（Gene Oncology， GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）分析进行功能富集，Homer鉴定转录因子基序，Cytoscape构建调控网络，并使用免疫组化进行验证，探讨其调控机制。

结果

SRCC沉默子主要分布于基因组远端基因间区（占37.06%）。与正常组织相比，SRCC中H3K27me3沉默子信号显著降低（95%

： 1.34~2.30，

=0.007），共鉴定出6 257个丢失位点（FDR

0.01）。CUT

Tag和RNA-seq整合分析显示，380个因沉默子丢失而上调的基因显著富集于免疫相关通路，如T细胞受体信号通路（

=4.2， 95%

： 2.8~6.3，

=0.00

）。免疫组化验证表明，转录因子

EHF

表达显著升高（

0.05）。

结论

SRCC中存在H3K27me3沉默子重塑现象，转录因子

EHF

可能在SRCC恶性进展中发挥关键作用。

Abstract

Objective‍　‍To draw the genome-wide distribution and remodeling characteristics of H3K27me3 silencers in signet-ring cell carcinoma of the stomach (SRCC) through epigenetic sequencing technology

and to investigate their roles in transcriptional regulation in order to elucidate the regulatory mechanism of SRCC malignant progression. Methods‍　‍The study was conducted on 35 gastric samples obtained by gastroendoscopic biopsy (15 normal and 20 SRCC tissues) from Department of Gastroenterology of Army Medical Center of PLA between January 2021 and December 2023. Multi-omics analyses

including assay for transposase-accessible chromatin with high-throughput sequencing （ATAC-seq)

cleavage under targets and tagmentation （CUT

Tag) and transcriptome sequencing （RNA-seq)

were performed to identify chromatin accessibility

H3K27me3 silencer regions

and transcriptional changes

with aid of Illumina NovaSeq 6000. H3K27me3 related differentially expressed genes (|Log

FC|

FDR

0.05) were screened using DESeq2. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis

were employed to analyze the enrichment function

and Homer was employed to identify transcription factor motifs. A regulatory network was constructed using Cytoscape

and then validated using immunohistochemistry to explore its regulatory mechanism.

Results

H3K27me3 silencers were primarily located in distal intergenic regions (37.06%) in SRCC. Compared with the normal tissues

SRCC showed a significant reduction in H3K27me3 silencer signals (95%

:1.34~2.30

=0.007) with 6 257 lost sites (FDR

0.01). Integrating CUT

Tag and RNA-seq revealed 380 up-regulated immune-related genes

particularly in T cell receptor signaling (

=4.2

95%

: 2.8~6.3

=0.002). Immunohistochemistry confirmed elevated expression of transcription factor EHF (

0.05). Conclusion‍　‍There is the remodeling of H3K27me3 silencers in SRCC

and EHF may potentially play a crucial role in the SRCC malignant progression.

关键词

Keywords

references

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