陆军军医大学学报 (Mar 2024)

Remodeling of histone H3K27me3-associated silencers upregulates PGK1 expression in gastric high-grade intraepithelial neoplasia

  • QIN Bijun,
  • TAN Yuting,
  • TAN Yuting,
  • CHU Zhaole

DOI
https://doi.org/10.16016/j.2097-0927.202310001
Journal volume & issue
Vol. 46, no. 6
pp. 597 – 607

Abstract

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Objective To characterize the silencers in genomic loci that were labeled by H3K37me3 modification in gastric high-grade intraepithelial neoplasia (HGIN) tissues, and identify their key downstream genes. Methods Gastric mucosa were collected from 48 donors, including 24 patients with HGIN and 24 healthy controls who underwent dndoscopic biopsy or endoscopic gastric mucosal dissection in our hospital. Genomic distribution of histone H3K27me3 modification was retrieved by targeted chromosome Cleavage Under Target & Tagmentation (CUT&Tag) sequencing. Bioinformatics analysis tools were used to compare the characteristics and differences of the silencer signals between the 2 types of tissues. The RNA sequencing data and the public high-through chromosome conformation capture (Hi-C) data were integrated to analyze the target genes regulated by silencer remodeling and their potential biological processes. Results Compared with normal gastric mucosal tissue, the number of H3K27me3 modifications and signal intensity in HGIN tissues were significantly reduced, which was manifested by global remodeling of H3K27me3 signals. High-throughput RNA sequencing and bioinformatics analysis showed that there were a total of 8 887 differentially expressed genes for HGIN tissues, including 4 335 up-regulated genes and 4 552 down-regulated ones, and among them, CTNNB1 and other oncogenes were significantly up-regulated. Integrated analysis of epigenomics and transcriptomics data reveled that extensive remodeling of silencers in HGIN. Loss of silencer may regulate the expression of metabolic genes related to amino acid biosynthesis, arginine and proline metabolism and glycolysis at the transcriptional level, such as phosphoglycerate kinase 1 (PGK1), which may promote development of gastric precancerous lesions. Conclusion Global remodeling of silencers, namely loss of H3K27me3 modification, is an epigenomic characteristics of HGIN tissue, which may lead to expression dysregulation of glycolysis and amino acid metabolism regulators, such as PGK1.

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