Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer.
Genome Res
; 34(5): 680-695, 2024 06 25.
Article
in En
| MEDLINE
| ID: mdl-38777607
ABSTRACT
Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq data from a compendium of GC cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq data, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) and the epithelial (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) states in GC. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 Comparisons with bulk and single-cell RNA-seq data sets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis-regulatory elements flanking upregulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of GC heterogeneity and progression.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach Neoplasms
/
Gene Expression Regulation, Neoplastic
/
Epithelial-Mesenchymal Transition
/
Machine Learning
Limits:
Humans
Language:
En
Journal:
Genome Res
/
Genome res
/
Genome research
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos