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

Summary 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.
Graphical Abstract
Highlights • 6mA deposition and erasure by mammalian Mettl4 and Alkbh4, respectively • Mettl4-deficient mice display craniofacial dysmorphism • 6mA triggers proteolysis of its cognate sensor proteins ASXL1 and MPND • Adversarial 6mA network architecture preserves Polycomb silencing
Kweon et al. reveal the molecular infrastructure of a mammalian DNA N6-methyladenine (6mA) methylation, erasure, and sensing system. Deposition of 6mA by the Mettl4 methyltransferase triggers the proteolytic destruction of its cognate sensor proteins, the histone H2A deubiquitinases ASXL1 and MPND, thus preserving Polycomb gene silencing.