Epigenetic memory loss in aging oligodendrocytes in the corpus callosum

Abstract

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.

The Glial or Neuronal Fate Choice of Oligodendrocyte Progenitors Is Modulated by Their Ability to Acquire an Epigenetic Memory

“…1 B). A similar effect was detected in vivo, after systemic administration of the HDAC inhibitor VPA, using a protocol that was previously reported to effectively increase global histone acetylation (Shen et al, 2005(Shen et al, , 2007. The most striking consequence of maintaining high levels of global histone acetylation in the brain of VPA-treated animals (supplemental Fig.…”

“…We have previously shown that the decision of neonatal cortical progenitors to acquire oligodendrocytic identity is dependent on histone deacetylase activity (Shen et al, 2005(Shen et al, , 2007. Because histone acetylation is functionally related to transcriptionally competent chromatin, we used gene expression profiling with Affymetrix microarrays to identify genes whose levels in differentiating oligodendrocyte progenitors were affected by this posttranslational modification of nucleosomes (supplemental Table 1, available at www.jneurosci.org as supplemental material).…”

“…It is well accepted that the identity of distinct cell types is affected by extracellular factors, whose signaling pathways modulate the expression of critical transcription factors. However, distinct cell types need to retain their own unique "memory" while responding to the extracellular environment (Shen et al, 2007). This memory is engraved in the cell's genome and is achieved by a series of posttranslational modifications of histones and DNA methylation (Buszczak and Spradling, 2006).…”

Higher-order Genome Organization in Human Disease

“…These observations are supported by the finding of reduced activity of several histone deacetylases in aged mice (Shen et al 2008). Aging-related structural defects in chromatin are also seen in yeast S. cerevisiae where instability of ribosomal repeats in the nucleolus have been associated with aging (Sinclair and Guarente 1997) and in Caenorhabditis elegans where both internal and peripheral heterochromatin blocks are lost during aging (Haithcock et al 2005).…”

“…This model is supported by the observed redistribution of the histone deacetylase SIRT1, which has previously been implicated in aging, in response to DNA damage and its association with genes, which are deregulated during aging (Oberdoerffer et al 2008). However, the model does not fully account for the observation that several epigenetic modifiers are lost, rather than redistributed within the genome, in normally and prematurely aged cells (Shen et al 2008;Pegoraro et al 2009). Furthermore, at least in the premature aging syndrome HGPS, DNA damage is a late event and is unlikely the trigger for the observed epigenetic changes because the loss of key chromatin proteins, such as NURD, occurs before DNA damage and is followed by changes in chromatin structure and epigenetic modifications and only eventually the appearance of DNA damage (Pegoraro et al 2009).…”