Remodeling of enhancers in high-grade epithelial dysplasia of gastric mucosa and its effect on expression of proliferation-related gene <italic style="font-style: italic">CD24</italic>

XUE Rui; PAN Yuwei; TAN Yuting; CHU Zhaole; LIU Biying; LI Xianfeng; WANG Tao; WANG Bin; ZHANG Xuan; SHEN Ai

doi:10.16016/j.2097-0927.202408113

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Remodeling of enhancers in high-grade epithelial dysplasia of gastric mucosa and its effect on expression of proliferation-related gene CD24

Monographic Reports | 更新时间：2025-03-11

- Remodeling of enhancers in high-grade epithelial dysplasia of gastric mucosa and its effect on expression of proliferation-related gene CD24
- Journal of Army Medical University Vol. 47, Issue 5, Pages: 426-434(2025)
- 作者机构：
  
  1.重庆大学医学院，重庆
  2.重庆大学附属肿瘤医院肝胆胰肿瘤中心，重庆
  3.陆军特色医学中心（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
  4.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 Natural Science Foundation for Distinguished Young Scholars of Chongqing(CSTC2019JCYJJQX0027)
- DOI：10.16016/j.2097-0927.202408113
  CLC： R394.3;R730.23;R735.2
- Received：26 August 2024，
  
  Revised：09 October 2024，
  
  Published：15 March 2025
- 稿件说明：
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薛锐，潘雨薇，谭玉婷，等.胃黏膜高级别上皮内瘤变组织的增强子重塑及其对增殖相关基因CD24表达的影响［J］.陆军军医大学学报，2025，47（05）：426-434.DOI：10.16016/j.2097-0927.202408113.

XUE R，PAN Y W，TAN Y T，et al.Remodeling of enhancers in high-grade epithelial dysplasia of gastric mucosa and its effect on expression of proliferation-related gene CD24［J］.J Army Med Univ，2025，47（05）：426-434.DOI：10.16016/j.2097-0927.202408113.
薛锐，潘雨薇，谭玉婷，等.胃黏膜高级别上皮内瘤变组织的增强子重塑及其对增殖相关基因CD24表达的影响［J］.陆军军医大学学报，2025，47（05）：426-434.DOI：10.16016/j.2097-0927.202408113. DOI：

XUE R，PAN Y W，TAN Y T，et al.Remodeling of enhancers in high-grade epithelial dysplasia of gastric mucosa and its effect on expression of proliferation-related gene CD24［J］.J Army Med Univ，2025，47（05）：426-434.DOI：10.16016/j.2097-0927.202408113. DOI：

摘要

目的

通过绘制胃黏膜高级别上皮内瘤变（high-grade intraepithelial neoplasia ，HGIN）组织中组蛋白H3K27ac修饰标记的增强子图谱，探究表观调控对HGIN发生发展的影响。

方法

收集2022年6月至2023年6月来自陆军特色医学中心消化内科的14例正常胃黏膜组织（Nor组）、31例胃黏膜高级别上皮内瘤变组织（HGIN组）和17例胃癌（gastric cancer，GC）组织（GC组），利用染色质靶向捕获测序（cleavage under targets and tagmentation，CUT&Tag）技术捕获组蛋白H3K27ac修饰的增强子区域；联合多组学分析筛选HGIN组织特异的活性增强子及其潜在调控的基因；采用免疫组化染色观察目的基因在不同类型临床样本中的表达差异，并通过CRISPR-dCas9基因编辑技术沉默活性增强子，观察目的基因的表达水平，并验证潜在调控关系。

结果

表观多组学测序数据质量较好，3组样本组间H3K27ac修饰的全基因组分布特征无显著差异，但H3K27ac增强子在HGIN、GC组织中发生明显重塑（

0.05）。联合转录组数据分析发现，增强子重塑可能上调HGIN组织增殖相关靶基因

CD24

表达；抑制增强子活性，则

CD24

表达水平显著降低（

0.05）。免疫组化结果显示，

CD24

表达与

Ki-67

呈正相关（

0.001）。

结论

H3K27ac标记的增强子重塑是HGIN的重要表观遗传学特征，H3K27ac标记的活性增强子上调

CD24

表达，可能促进HGIN增殖。

Abstract

Objective‍　‍To identify the enhancer profile marked by histone H3K27ac modification in high-grade intraepithelial neoplasia (HGIN) in order to reveal the novel regulatory mechanism of HGIN pathogensis. Methods‍　‍Gastric tissue samples were collected from Department of Gastroenterology of Army Medical Center of PLA between June 2022 and June 2023

including 14 normal gastric tissues (Nor group)

31 HGIN tissues (HGIN group) and 17 gastric cancer tissues (GC group). Cleavage under targets and tagmentation (CUT

Tag) technique was employed to capture enhancer regions modified by histone H3K27ac. Multi-omics analysis was performed to identify HGIN-specific active enhancers and their potentially regulated genes. Immunohistochemical profiling was performed to assess differential expression of the gene of interest across clinically stratified specimens

combined with CRISPR-dCas9-mediated ablation of active enhancers to monitor the gene of interest transcriptional dynamics and validate enhancer-mediated regulatory mechanisms. Results‍　‍Epigenomic sequencing obtained the data with excellent quality

and indicated that obvious remodeling was observed in H3K27ac enhancers in HGIN and GC groups (

0.05)

though no significant difference in the genome-wide distribution of H3K27ac modification among the 3 groups.Combining transcriptome data revealed that enhancer remodeling may up-regulate the expression of the proliferation-related target gene

CD24

in the HGIN tissue; while

inhibiting enhancer activity can notably reduce

CD24

expression level (

0.05). Immunohistochemical assay displayed a positive correlati

on between the expression levels of

CD24

and

Ki-67

(

0.001). Conclusion‍　‍The remodeling of H3K27ac enhancer represents a significant epigenetic feature of the transformation from normal condition to HGIN. Remodeling of H3K27ac enhancer up-regulates

CD24

which may facilitate the abnormal proliferation of gastric epithelial cells.

关键词

Keywords

references

AJANI J A ， D’AMICO T A ， BENTREM D J ， et al . Gastric cancer， version 2.2022， NCCN clinical practice guidelines in oncology ［J］. J Natl Compr Canc Netw ， 2022 ， 20 （ 2 ）： 167 - 192 . DOI： 10.6004/jnccn.2022.0008 http://dx.doi.org/10.6004/jnccn.2022.0008 .

国家消化系疾病临床医学研究中心（上海），国家消化道早癌防治中心联盟，中华医学会消化病学分会幽门螺杆菌学组，等 . 中国胃黏膜癌前状态和癌前病变的处理策略专家共识（2020年）［J］. 中华消化杂志， 2020 ， 40 （ 11 ）： 731 - 741 . DOI： 10.3760/cma.j.cn311367-20200915-00554 http://dx.doi.org/10.3760/cma.j.cn311367-20200915-00554 .

National Clinical Research Center for Digestive Disease （Shanghai）， National Early Gastrointestinal Center Prevention& Treatment Center Alliance ， Helicobacter Pylori Group of Chinese Society of Gastroenterology from Chinese Medical Association ， et al . Chinese consensus on management of gastric epithelial precancerous conditions and lesions （2020）［J］. Chin J Dig ， 2020 ， 40 （ 11 ）： 731 - 741 . DOI： 10.3760/cma.j.cn311367-20200915-00554 http://dx.doi.org/10.3760/cma.j.cn311367-20200915-00554 .

于颖彦，朱正纲 . 第5版 WHO消化道肿瘤分类与分期解读：胃肿瘤［J］. 外科理论与实践， 2020 ， 25 （ 3 ）： 207 - 210 . DOI： 10.16139/j.1007-9610.2020.03.007 http://dx.doi.org/10.16139/j.1007-9610.2020.03.007 .

YU Y Y ， ZHU Z G . Interpretation of the 5th edition WHO classificaion and staging of tumors of digestive system： gastric tumors ［J］. J Surg Concepts Pract ， 2020 ， 25 （ 3 ）： 207 - 210 . DOI： 10.16139/j.1007-9610.2020.03.007 http://dx.doi.org/10.16139/j.1007-9610.2020.03.007 .

JEON J W ， KIM S J ， JANG J Y ， et al . Clinical outcomes of endoscopic resection for low-grade dysplasia and high-grade dysplasia on gastric pretreatment biopsy： Korea ESD study group ［J］. Gut Liver ， 2021 ， 15 （ 2 ）： 225 - 231 . DOI： 10.5009/gnl19275 http://dx.doi.org/10.5009/gnl19275 .

SMYTH E C ， NILSSON M ， GRABSCH H I ， et al . Gastric cancer ［J］. Lancet ， 2020 ， 396 （ 10251 ）： 635 - 648 . DOI： 10.1016/S0140-6736（20）31288-5 http://dx.doi.org/10.1016/S0140-6736（20）31288-5 .

中华人民共和国国家卫生健康委员会医政医管局 . 胃癌诊疗指南（2022年版）［J］. 中华消化外科杂志， 2022 ， 21 （ 9 ）： 1137 - 1164 . DOI： 10.3760/cma.j.cn115610-20220726-00432 http://dx.doi.org/10.3760/cma.j.cn115610-20220726-00432 .

Bureau of Medical Administration of National Health Commission of the People’s Republic of China . Standardiza-tion for diagnosis and treatment of gastric cancer （2022 edition）［J］. Chin J Dig Surg ， 2022 ， 21 （ 9 ）： 1137 - 1164 . DOI： 10.3760/cma.j.cn115610-20220726-00432 http://dx.doi.org/10.3760/cma.j.cn115610-20220726-00432 .

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 http://dx.doi.org/10.16016/j.2097-0927.202210071 .

LIU W K ， WU L Y ， YU B ， et al . Reprogramming characteristics of H3K27ac-marked enhancer in gastric intestinal metaplasia and its transcriptional regulatory mechanism ［J］. J Army Med Univ ， 2023 ， 45 （ 6 ）： 500 - 509 . DOI： 10.16016/j.2097-0927.202210071 http://dx.doi.org/10.16016/j.2097-0927.202210071 .

吴林育 . 胃黏膜肠化的H3K27me3沉默子重塑特征及肠化调控因子ATOH1的初步功能鉴定［D］. 重庆：陆军军医大学， 2023 . DOI： 10.27001/d.cnki.gtjyu.2023.000311 http://dx.doi.org/10.27001/d.cnki.gtjyu.2023.000311 .

WU L Y . Remodeling characteristics of H3K27me3 silencing in intestinal metaplasia of gastric mucosa and preliminary functional identification of ATOH1， a regulator of intestinal metaplasia ［D］. Chongqing ： Army Medical University ， 2023 . DOI： 10.27001/d.cnki.gtjyu.2023.000311 http://dx.doi.org/10.27001/d.cnki.gtjyu.2023.000311 .

YAO J ， CHEN J ， LI L Y ， et al . Epigenetic plasticity of enhancers in cancer ［J］. Transcription ， 2020 ， 11 （ 1 ）： 26 - 36 . DOI： 10.1080/21541264.2020.1713682 http://dx.doi.org/10.1080/21541264.2020.1713682 .

CALO E ， WYSOCKA J . Modification of enhancer chromatin： what， how， and why？［J］. Mol Cell ， 2013 ， 49 （ 5 ）： 825 - 837 . DOI： 10.1016/j.molcel.2013.01.038 http://dx.doi.org/10.1016/j.molcel.2013.01.038 .

FURLONG E E M ， LEVINE M . Developmental enhancers and chromosome topology ［J］. Science ， 2018 ， 361 （ 6409 ）： 1341 - 1345 . DOI： 10.1126/science.aau0320 http://dx.doi.org/10.1126/science.aau0320 .

SCHOENFELDER S ， FRASER P . Long-range enhancer-promoter contacts in gene expression control ［J］. Nat Rev Genet ， 2019 ， 20 （ 8 ）： 437 - 455 . DOI： 10.1038/s41576-019-0128-0 http://dx.doi.org/10.1038/s41576-019-0128-0 .

CORCES M R ， TREVINO A E ， HAMILTON E G ， et al . An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues ［J］. Nat Methods ， 2017 ， 14 （ 10 ）： 959 - 962 . DOI： 10.1038/nmeth.4396 http://dx.doi.org/10.1038/nmeth.4396 .

CORREA P . A human model of gastric carcinogenesis ［J］. Cancer Res . 1988 Jul 1 ； 48 （ 13 ）： 3554 - 3560 .

秦苾珺，谭玉婷，储召乐，等 . 组蛋白H3K27me3沉默子重塑上调胃黏膜高级别上皮内瘤变磷酸甘油醛激酶1表达［J］. 陆军军医大学学报， 2024 ， 46 （ 6 ）： 597 - 607 . DOI： 10.16016/j.2097-0927.202310001 http://dx.doi.org/10.16016/j.2097-0927.202310001 .

QIN B J ， TAN Y T ， CHU Z L ， et al . Remodeling of histone H3K27me3-associated silencers upregulates PGK1 expression in gastric high-grade intraepithelial neoplasia ［J］. J Army Med Univ ， 2024 ， 46 （ 6 ）： 597 - 607 . DOI： 10.16016/j.2097-0927.202310001 http://dx.doi.org/10.16016/j.2097-0927.202310001 .

YANG Y ， ZHU G M ， YANG L ， et al . Targeting CD24 as a novel immunotherapy for solid cancers ［J］. Cell Commun Signal ， 2023 ， 21 （ 1 ）： 312 . DOI： 10.1186/s12964-023-01315-w http://dx.doi.org/10.1186/s12964-023-01315-w .

KRISTIANSEN G ， SAMMAR M ， ALTEVOGT P . Tumour biological aspects of CD24， a mucin-like adhesion molecule ［J］. J Mol Histol ， 2004 ， 35 （ 3 ）： 255 - 262 . DOI： 10.1023/b： hijo.0000032357.16261.c5 http://dx.doi.org/10.1023/b：hijo.0000032357.16261.c5 .

ZHAO K ， WU C F ， LI X J ， et al . From mechanism to therapy： the journey of CD24 in cancer ［J］. Front Immunol ， 2024 ， 15 ： 1401528 . DOI： 10.3389/fimmu.2024.1401528 http://dx.doi.org/10.3389/fimmu.2024.1401528 .

TARHRIZ V ， BANDEHPOUR M ， DASTMALCHI S ， et al . Overview of CD24 as a new molecular marker in ovarian cancer ［J］. J Cell Physiol ， 2019 ， 234 （ 3 ）： 2134 - 2142 . DOI： 10.1002/jcp.27581 http://dx.doi.org/10.1002/jcp.27581 .

SAGIV E ， ARBER N . The novel oncogene CD24 and its arising role in the carcinogenesis of the GI tract： from research to therapy ［J］. Expert Rev Gastroenterol Hepatol ， 2008 ， 2 （ 1 ）： 125 - 133 . DOI： 10.1586/17474124.2.1.125 http://dx.doi.org/10.1586/17474124.2.1.125 .

SANO A ， KATO H ， SAKURAI S ， et al . CD24 expression is a novel prognostic factor in esophageal squamous cell carcinoma ［J］. Ann Surg Oncol ， 2009 ， 16 （ 2 ）： 506 - 514 . DOI： 10.1245/s10434-008-0252-0 http://dx.doi.org/10.1245/s10434-008-0252-0 .

ATHANASSIADOU P ， GRAPSA D ， GONIDI M ， et al . CD24 expression has a prognostic impact in breast carcinoma ［J］. Pathol Res Pract ， 2009 ， 205 （ 8 ）： 524 - 533 . DOI： 10.1016/j.prp.2009.01.008 http://dx.doi.org/10.1016/j.prp.2009.01.008 .

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⁰

Remodeling of enhancers in high-grade epithelial dysplasia of gastric mucosa and its effect on expression of proliferation-related gene CD24

DOI：10.16016/j.2097-0927.202408113

摘要

Abstract

关键词

Keywords

references