Investigating the role of de novo DNA methylation in regulating liver metabolism

Youngson NA1, Prates KV1, Yao S1, McRae AF2 and Morris MJ1

  1. School of Medical Sciences, UNSW Sydney.
  2. Institute for Molecular Bioscience, The University of Queensland.

The de novo DNA methyltransferases are required for development as their constitutive deletion in mice results in lethality either in the late embryonic period (Dnmt3a) or in the first weeks after birth (Dnmt3b). Beyond development, post-natal DNA methylation changes have been identified that associate with disease states or particular diets. However, despite hundreds of studies that associate de novo methylation changes in mammals, a functional requirement for those DNA methylation changes is still not proven. Uncovering the true role of DNA methylation in disease is vital for understanding pathogenesis, and in directing the development of therapies. If DNA methylation is just a consequence of, or a minor player in, disease associated transcriptional change, then future epigenetic studies in this area should focus on other molecules such as histone tail modifications. To investigate this issue we have generated mice that are homozygous mutants for both Dnmt3a and Dnmt3b in post-natal liver. These mice are viable and fertile. Here we present data on the requirement for liver de novo methylation for systemic glucose metabolism, in control and obese mice. Our model also sheds light on how in vivo inhibition of de novo DNA methylation in liver affects other epigenetic regulatory systems, and systematic physiology and behaviour.