Transition to naïve human pluripotency mirrors pan-cancer DNA hypermethylation

Nat Commun. 2020 Jul 22;11(1):3671. doi: 10.1038/s41467-020-17269-3.

Abstract

Epigenetic reprogramming is a cancer hallmark, but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. Here we show that resetting from primed to naïve human pluripotency results in acquisition of a DNA methylation landscape mirroring the cancer DNA methylome, with gradual hypermethylation of bivalent developmental genes. We identify a dichotomy between bivalent genes that do and do not become hypermethylated, which is also mirrored in cancer. We find that loss of H3K4me3 at bivalent regions is associated with gain of methylation. Additionally, we observe that promoter CpG island hypermethylation is not restricted solely to emerging naïve cells, suggesting that it is a feature of a heterogeneous intermediate population during resetting. These results indicate that transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories, which implicates reprogramming and the pluripotency network as a central hub in cancer formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic / genetics*
  • Cellular Reprogramming*
  • Coculture Techniques
  • CpG Islands / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • DNA Methyltransferase 3A
  • Epigenesis, Genetic*
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Histones / genetics
  • Histones / metabolism
  • Human Embryonic Stem Cells
  • Humans
  • Mice
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism
  • Neoplasms / genetics*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Small Interfering / metabolism

Substances

  • DNMT3A protein, human
  • Histones
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • histone H3 trimethyl Lys4
  • Mixed Function Oxygenases
  • TET1 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A