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O3‐05‐06: Epigenetic regulation of tau gene expression
Author(s) -
Meredith Gavin,
D'Ippolito Anthony,
Marnellos George,
Phiel Christopher
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1421
Subject(s) - neurodegeneration , biology , dna methylation , gene , microbiology and biotechnology , epigenetics , gene expression , hyperphosphorylation , genomic dna , genetics , kinase , disease , medicine , pathology
Background: The formation of neurofibrillary tangles is one of the characteristic features in the brains of patients with Alzheimer’s disease. Hyperphosphorylation of tau protein by kinases such as Gsk-3 have been implicated in neurodegeneration. As such, small molecule inhibitors of Gsk-3 have been pursued as a potential therapeutics in the effort to slow or prevent neurodegeneration. Methods: Taq Man qPCR was performed on RNA isolated from wild-type and Gsk-3-deficient mouse embryonic stem cells. A role for Gsk-3 in DNA methylation at the Mapt locus was revealed by isolation of total genomic methylated DNA from wild-type and Gsk-3-deficient mouse embryonic stem cells using the Methyl Miner kit. Libraries of methylated DNAwere created, and whole-genome sequencing was performed on a SOLiD machine. Bioinformatic analysis of data identified regions of the mouse genome that were differentially methylated in the Gsk-3-deficient cells.Results:Here we present data showing that Gsk-3 activity also regulates the expression of tau mRNA. Tau mRNA expression is reduced by more than 80% in Gsk-3 deficient cells. This reduction in gene expression is accompanied by changes in DNA methylation at the Mapt locus. Conclusions: These data suggest that inhibition of Gsk-3 activity not only affects tau phosphorylation, but also provides a second layer of possible beneficial effects by reducing the expression of tau mRNA. Finally, the role of DNA methylation in regulating tau gene expression affords a novel therapeutic approach to preventing tangle-related neurodegeneration.