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Updated: Dec 23, 2025

Immunostaining for DNA Modifications: Computational Analysis of Confocal Images
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DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex

Vishal Nanavaty1, Elizabeth W Abrash1, Changjin Hong2

  • 1Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Molecular Cell
|April 26, 2020
PubMed

Insights

DNA methylation loss in cancer cells alters mRNA processing by promoting proximal polyadenylation site usage. This DNA methylation-regulated alternative polyadenylation (APA) mechanism impacts transcriptome diversity and cancer treatment strategies.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are frequently dysregulated in cancer.
  • These processes have traditionally been studied as independent mechanisms influencing gene expression.

Purpose of the Study:

  • To investigate the interplay between DNA methylation and mRNA APA.
  • To elucidate a novel DNA methylation-regulated APA mechanism.

Main Methods:

  • Comparative analysis of genome-wide DNA methylation and polyadenylation site usage in DNA methylation-competent versus deficient cells.
  • Functional studies involving CTCF binding site deletion and RAD21 cohesin complex protein depletion.
  • Validation using The Cancer Genome Atlas (TCGA) data.

Main Results:

  • Removal of DNA methylation facilitates CTCF binding and cohesin complex recruitment, leading to chromatin looping and proximal polyadenylation site usage.
  • Disruption of CTCF binding or RAD21 cohesin levels restores distal polyadenylation site usage in demethylated contexts.
  • In vivo data from TCGA confirms the correlation between DNA methylation status and mRNA polyadenylation isoform expression.

Conclusions:

  • A novel mechanism links DNA methylation status to mRNA APA, impacting transcriptome diversity.
  • Aberrant DNA methylation in cancer influences APA, affecting gene expression patterns.
  • Understanding this mechanism offers insights into the consequences of global DNA methylation inhibition as a cancer therapy.
Keywords:
CTCFalternative cleavage and polyadenylationcohesingene-body DNA methylationtranscriptome diversity

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