Epigenetic memory loss in aging oligodendrocytes in the corpus callosum.
In this study, we address the hypothesis that aging modifies the intrinsic properties of oligodendrocytes, the myelin-forming cells of the brain. According to our model, an "epigenetic memory" is stored in the chromatin of the oligodendrocyte lineage cells and is responsible for the maintenance of a mature phenotype, characterized by low levels of expression of transcriptional inhibitors. We report here an age-related decline of histone deacetylation and methylation, the molecular mechanisms responsible for the establishment and maintenance of this "epigenetic memory" of the differentiated state. We further show that lack of histone methylation and increased acetylation in mature oligodendrocytes are associated with global changes in gene expression, that include the re-expression of bHLH inhibitors (i.e. Hes5 and Id4) and precursor markers (i.e. Sox2). These changes characteristic of the "aging" oligodendrocytes can be recapitulated in vitro, by treating primary oligodendrocyte cultures with histone deacetylase inhibitors. Thus, we conclude that the "epigenetic memory loss" detected in white matter tracts of older mice induces global changes of gene expression that modify the intrinsic properties of aged oligodendrocytes and may functionally modulate the responsiveness of these cells to external stimuli.
Shen
Siming
S
Department Neuroscience and Cell Biology, Robert Wood Johnson Medical School, UMDNJ, Piscataway, NJ 08854, USA.
Liu
Aixiao
A
Li
Jiadong
J
Wolubah
Candy
C
Casaccia-Bonnefil
Patrizia
P
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D000071183:Autophagy-Related Proteins; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003337:Corpus Callosum / Q000166:cytology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000502:physiology*; D051381:Rats; D055748:SOXB1 Transcription Factors; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism
D000071183:Autophagy-Related Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C428743:Rb1cc1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C527784:Sox2 protein, rat; D015534:Trans-Activators; D006655:Histone Deacetylases