The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders

Transl Psychiatry. 2019 Feb 6;9(1):34. doi: 10.1038/s41398-019-0367-z.


Adolescent alcohol drinking is known to contribute to the development and severity of alcohol use disorders (AUDs) later in adulthood. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical for brain development and synaptic plasticity. One such lncRNA is natural occurring brain-derived neurotrophic factor antisense (BDNF-AS) that has been shown to regulate BDNF expression. The role of BDNF-AS lncRNA in the molecular mechanisms of AUD is unknown. Here, we evaluated the expression and functional role of BDNF-AS in postmortem amygdala of either early onset or late onset alcoholics (individuals who began drinking before or after 21 years of age, respectively) and age-matched control subjects. BDNF-AS expression is increased in early onset but not in late onset AUD amygdala and appears to be regulated epitranscriptomically via decreased N6-methyladenosine on BDNF-AS. Upregulation of BDNF-AS is associated with a significant decrease in BDNF expression and increased recruitment of EZH2, which deposits repressive H3K27 trimethylation (H3K27me3) at regulatory regions in the BDNF gene in the early onset AUD group. Drinking during adolescence also contributed to significant decreases in activity-regulated cytoskeleton-associated protein (ARC) expression which also appeared to be mediated by increased EZH2 deposition of repressive H3K27me3 at the ARC synaptic activity response element. These results suggest an important role for BDNF-AS in the regulation of synaptic plasticity via epigenetic reprogramming in the amygdala of AUD subjects who began drinking during adolescence.

Publication types

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

MeSH terms

  • Alcoholism / genetics*
  • Amygdala / physiopathology*
  • Brain-Derived Neurotrophic Factor / genetics*
  • Case-Control Studies
  • Cytoskeletal Proteins / genetics
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neuronal Plasticity / physiology
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*


  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • RNA, Long Noncoding
  • BDNF protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein