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Epigenetic Silencing of Netrin is associated with Memory Loss by High Methionine, Low Folate and Vitamin B 6 /B 12 containing diet
Author(s) -
Kalani Anuradha,
Kamat Pradip,
Lominadze David,
Tyagi Neetu
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.996.6
Subject(s) - epigenetics , dna methylation , methylation , gene silencing , biology , homocysteine , methionine , endocrinology , gene expression , gene , genetics , amino acid
High methylation is known to silence genes of many proteins, which can be associated with changes in cognitive function. Loss of memory due to epigenetic modifications, called memory‐epigenetics was studied. We hypothesized that high methionine (met) diet leads to memory impairment by increasing global DNA methylation and therefore, silencing the netrin gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed diet containing excess met (1.2%), low‐folate (0.08 mg/kg), vitamin B 6 (0.01 mg/kg), and B 12 (10.4 μg/kg) for 6 weeks. Mice were weekly examined for memory function. Our results using a passive avoidance test confirmed a loss in fear motivated long‐term memory starting from 4 th week of diet. The loss of memory was associated with an increase in global DNA methylation in brain samples of mice fed with diet. We found a time‐dependent decrease in netrin protein expression and an increase in methylation of netrin gene promoter, defined by restriction digestion and PCR analysis, in mice fed with diet. The increase in methylation of netrin gene promoter was validated by high resolution melting analysis. In addition, it was found that the level of netrin receptor DCC (deleted in colon cancer) was decreased in mice on diet. Taken together, these results confirm that diet containing high met, low folate and vitamin B 6 /B 12 can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin level due to hypermethylation of its gene promoter can be associated with memory loss. This work was supported by NIH grant HL107640‐NT.