DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex

Vishal Nanavaty, Elizabeth W. Abrash, Changjin Hong, Sunho Park, Emily E. Fink, Zhuangyue Li, Thomas J. Sweet, Jeffrey M. Bhasin, Srinidhi Singuri, Byron H. Lee, Tae Hyun Hwang, Angela H. Ting

Research output: Contribution to journalArticle

Abstract

Dysregulation of DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are both prevalent in cancer and have been studied as independent processes. We discovered a DNA methylation-regulated APA mechanism when we compared genome-wide DNA methylation and polyadenylation site usage between DNA methylation-competent and DNA methylation-deficient cells. Here, we show that removal of DNA methylation enables CTCF binding and recruitment of the cohesin complex, which, in turn, form chromatin loops that promote proximal polyadenylation site usage. In this DNA demethylated context, either deletion of the CTCF binding site or depletion of RAD21 cohesin complex protein can recover distal polyadenylation site usage. Using data from The Cancer Genome Atlas, we authenticated the relationship between DNA methylation and mRNA polyadenylation isoform expression in vivo. This DNA methylation-regulated APA mechanism demonstrates how aberrant DNA methylation impacts transcriptome diversity and highlights the potential sequelae of global DNA methylation inhibition as a cancer treatment.

Original languageEnglish (US)
Pages (from-to)752-764.e6
JournalMolecular cell
Volume78
Issue number4
DOIs
StatePublished - May 21 2020
Externally publishedYes

Keywords

  • CTCF
  • alternative cleavage and polyadenylation
  • cohesin
  • gene-body DNA methylation
  • transcriptome diversity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Nanavaty, V., Abrash, E. W., Hong, C., Park, S., Fink, E. E., Li, Z., Sweet, T. J., Bhasin, J. M., Singuri, S., Lee, B. H., Hwang, T. H., & Ting, A. H. (2020). DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex. Molecular cell, 78(4), 752-764.e6. https://doi.org/10.1016/j.molcel.2020.03.024