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Prediction and Validation of Gene Regulatory Elements Activated During Retinoic Acid Induced Embryonic Stem Cell Differentiation
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Cell-specific expression of the FAP gene is regulated by enhancer elements.

Dina V Antonova1, Dmitry A Gnatenko1, Elena S Kotova2

  • 1Gene Immunooncotherapy Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Department of Genomics and Postgenomic Technologies, Russian Academy of Sciences, Moscow, Russia.

Frontiers in Molecular Biosciences
|February 24, 2023
PubMed
Summary

Mechanisms regulating Fibroblast Activation Protein (FAP) expression in cancer cells are poorly understood. This study identifies novel enhancer elements and epigenetic marks controlling FAP gene transcription, revealing potential therapeutic targets.

Keywords:
FAPH3K27acenhancerfibroblast activation protein alphapromoterstat3

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Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Fibroblast Activation Protein (FAP) is upregulated in various cancers, making it a promising therapeutic target.
  • The precise mechanisms governing cell-specific FAP gene expression remain largely unelucidated.
  • Previous studies indicate promoter activity alone does not fully explain FAP expression levels.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling cell-specific Fibroblast Activation Protein (FAP) gene expression.
  • To identify novel genetic elements and epigenetic modifications involved in FAP transcription.
  • To explore potential therapeutic strategies targeting FAP regulation in cancer.

Main Methods:

  • Analysis of FAP promoter variants and mRNA expression across different cell lines.
  • Chromatin immunoprecipitation (ChIP) to assess epigenetic marks (e.g., H3K27ac) in FAP-positive and FAP-negative cells.
  • Functional assays to evaluate enhancer activity of identified elements (E1, E2) on FAP promoter variants.

Main Results:

  • No direct correlation found between FAP promoter activity and endogenous FAP mRNA levels.
  • Two enhancer-like elements (E1 and E2) within the FAP gene locus were identified.
  • Specific enrichment of H3K27ac marks at these enhancers in FAP-expressing cells, demonstrating enhancer activity.
  • Transcription factors AP-1, CEBPB, and STAT3 are implicated in FAP activation.
  • A potential positive feedback loop between FAP and STAT3 was hypothesized.

Conclusions:

  • Epigenetic regulation via enhancer elements, not solely promoter activity, drives cell-specific FAP expression.
  • The identified enhancers (E1, E2) and associated epigenetic marks are crucial for FAP transcription.
  • The FAP-STAT3 feedback loop presents a novel avenue for cancer therapy development.