Extra-coding RNAs regulate neuronal DNA methylation dynamics

Nat Commun. 2016 Jul 7;7:12091. doi: 10.1038/ncomms12091.


Epigenetic mechanisms such as DNA methylation are essential regulators of the function and information storage capacity of neurons. DNA methylation is highly dynamic in the developing and adult brain, and is actively regulated by neuronal activity and behavioural experiences. However, it is presently unclear how methylation status at individual genes is targeted for modification. Here, we report that extra-coding RNAs (ecRNAs) interact with DNA methyltransferases and regulate neuronal DNA methylation. Expression of ecRNA species is associated with gene promoter hypomethylation, is altered by neuronal activity, and is overrepresented at genes involved in neuronal function. Knockdown of the Fos ecRNA locus results in gene hypermethylation and mRNA silencing, and hippocampal expression of Fos ecRNA is required for long-term fear memory formation in rats. These results suggest that ecRNAs are fundamental regulators of DNA methylation patterns in neuronal systems, and reveal a promising avenue for therapeutic targeting in neuropsychiatric disease states.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / metabolism*
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • CpG Islands
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Fear / physiology
  • Humans
  • Injections, Intraventricular
  • Male
  • Neurons / cytology
  • Neurons / metabolism*
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / metabolism
  • Oncogene Proteins v-fos / antagonists & inhibitors
  • Oncogene Proteins v-fos / genetics*
  • Oncogene Proteins v-fos / metabolism
  • Primary Cell Culture
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Stereotaxic Techniques


  • Oligonucleotides, Antisense
  • Oncogene Proteins v-fos
  • RNA, Messenger