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Traumatic stress‐induced persistent changes in DNA methylation regulate neuropeptide Y expression in rat jejunum
Author(s) -
Sagarkar S.,
Mahajan S.,
Choudhary A. G.,
Borkar C. D.,
Kokare D. M.,
Sakharkar A. J.
Publication year - 2017
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13074
Subject(s) - dna methylation , neuropeptide y receptor , epigenetics , biology , jejunum , dna methyltransferase , dna demethylation , endocrinology , medicine , gene expression , methyltransferase , methylation , neuropeptide , dna , gene , genetics , receptor
Background 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. Methods 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. Key Results Minimal traumatic brain injury reduced the gut motility 48 hours and 30 days after trauma. The expression of DNA methyltransferase isoforms ( DNMT 1, DNMT 3a, and DNMT 3b) was altered in the jejunum 48 hours and 30 days after MTBI . However, the mRNA levels of growth arrest and DNA damage 45 ( GADD 45) isoforms, GADD 45a, and GADD 45b, which are believed to be involved in active DNA demethylation, initially decreased at 48 hours but subsequently increased after 30 days of trauma. Similarly, DNA hypomethylation at the NPY promoter region in the jejunum was correlated with the increase in NPY mRNA and protein levels 30 days post‐trauma. On the other hand, DNA hypomethylation at 48 hours 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. Conclusions & Inferences 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.