Traumatic stress-induced persistent changes in DNA methylation regulate neuropeptide Y expression in rat jejunum.

Abstract

Stress-induced chronic neuropsychiatric conditions such as anxiety are often co-morbid with gastrointestinal malfunctions. While we find enduring anxiety-like symptoms following minimal traumatic brain injury (MTBI) in rats, gastrointestinal consequences of MTBI remain elusive. In this study, we examined the effects of MTBI on a major gut peptide, neuropeptide Y (NPY) and gut motility. DNA methylation was studied as a possible epigenetic mechanism operative in the regulation of NPY expression in the gut. Minimal traumatic brain injury reduced the gut motility 48hours and 30days after trauma. The expression of DNA methyltransferase isoforms (DNMT1, DNMT3a, and DNMT3b) was altered in the jejunum 48hours and 30days after MTBI. However, the mRNA levels of growth arrest and DNA damage 45 (GADD45) isoforms, GADD45a, and GADD45b, which are believed to be involved in active DNA demethylation, initially decreased at 48hours but subsequently increased after 30days of trauma. Similarly, DNA hypomethylation at the NPY promoter region in the jejunum was correlated with the increase in NPY mRNA and protein levels 30days post-trauma. On the other hand, DNA hypomethylation at 48hours was associated with a decline in NPY expression. Treatment with 5-azacytidine (5-AzaC), a DNMT inhibitor, retarded DNA methylation and restored the NPY mRNA levels in the jejunum of MTBI-induced rats. These results suggest that DNA demethylation could be operative as an epigenetic mechanism in the long-term regulation of NPY gene expression to alter the gut motility during traumatic stress.