An Adversarial DNA N6-Methyladenine-Sensor Network Preserves Polycomb Silencing

Mol Cell. 2019 Jun 20;74(6):1138-1147.e6. doi: 10.1016/j.molcel.2019.03.018. Epub 2019 Apr 11.

Abstract

Adenine N6 methylation in DNA (6mA) is widespread among bacteria and phage and is detected in mammalian genomes, where its function is largely unexplored. Here we show that 6mA deposition and removal are catalyzed by the Mettl4 methyltransferase and Alkbh4 dioxygenase, respectively, and that 6mA accumulation in genic elements corresponds with transcriptional silencing. Inactivation of murine Mettl4 depletes 6mA and causes sublethality and craniofacial dysmorphism in incross progeny. We identify distinct 6mA sensor domains of prokaryotic origin within the MPND deubiquitinase and ASXL1, a component of the Polycomb repressive deubiquitinase (PR-DUB) complex, both of which act to remove monoubiquitin from histone H2A (H2A-K119Ub), a repressive mark. Deposition of 6mA by Mettl4 triggers the proteolytic destruction of both sensor proteins, preserving genome-wide H2A-K119Ub levels. Expression of the bacterial 6mA methyltransferase Dam, in contrast, fails to destroy either sensor. These findings uncover a native, adversarial 6mA network architecture that preserves Polycomb silencing.

Keywords: 6mA; ALKBH1; ALKBH4; ASXL1; DNA methylation; METTL4; MPND; TRIP12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / metabolism
  • AlkB Homolog 4, Lysine Demethylase / genetics*
  • AlkB Homolog 4, Lysine Demethylase / metabolism
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / metabolism
  • Craniofacial Abnormalities / pathology
  • DNA / genetics*
  • DNA / metabolism
  • DNA Methylation
  • Deubiquitinating Enzymes / genetics
  • Deubiquitinating Enzymes / metabolism
  • Female
  • Gene Silencing
  • Genes, Lethal
  • Histones / genetics
  • Histones / metabolism
  • Inbreeding
  • Male
  • Methyltransferases / deficiency
  • Methyltransferases / genetics*
  • Mice
  • Mice, Knockout
  • Proteolysis
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Site-Specific DNA-Methyltransferase (Adenine-Specific) / genetics
  • Site-Specific DNA-Methyltransferase (Adenine-Specific) / metabolism
  • Transcription, Genetic
  • Ubiquitin / genetics
  • Ubiquitin / metabolism

Substances

  • Asxl1 protein, mouse
  • Bacterial Proteins
  • Histones
  • Repressor Proteins
  • Ubiquitin
  • DNA
  • ALKBH4 protein, mouse
  • AlkB Homolog 4, Lysine Demethylase
  • Methyltransferases
  • Dam methyltransferase
  • Site-Specific DNA-Methyltransferase (Adenine-Specific)
  • Deubiquitinating Enzymes
  • Adenine
  • 6-methyladenine