Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis

Abstract

The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting modulation of adult neurogenesis is unknown. Here we identify Gadd45b as a neural activity–induced immediate early gene in mature hippocampal neurons. Mice with Gadd45b deletion exhibit specific deficits in neural activity–induced proliferation of neural progenitors and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of corresponding genes critical for adult neurogenesis, including brain-derived neurotrophic factor and fibroblast growth factor. Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain.

Epigenetic regulation of aging stem cells

“…This review will focus primarily on changes in histone modifications. However, we also note that regulators of DNA methylation are required for the function of a variety of adult stem cells (Zhao et al, 2003;Ma et al, 2009;Trowbridge et al, 2009;Sen et al, 2010;Trowbridge and Orkin, 2010;Wu et al, 2010), and that they complex with chromatin modifiers to elicit changes in chromatin state (Jones et al, 1998;Nan et al, 1998;Fuks et al, 2003). In addition, chromatin remodeling factors are also important for stem and progenitor cell function (Lessard et al, 2007;Ho et al, 2009;Ho and Crabtree, 2010), suggesting that several epigenetic mechanisms could coordinately control adult stem cell gene expression programs during organismal aging.…”

CpG Methylation in Neurons: Message, Memory, or Mask?

“…Recent work by Métivier et al (2008) and Kangaspeska et al (2008) reveals a methylating-demethylating cycle of periodicity in the range of 30-50 min in mitotic cells. Another study found demethylation can occur between 4 and 120 h in post-mitotic neurons (Ma et al, 2009). Demethylation in these studies is characterized by site specificity (ie, to an individual cytosine address) and is coordinated with proteins involved in the removal of methylated cytosine in the aforementioned two step enzymatic process of deamination/base-excision.…”

“…Additional neuronal studies manipulating DNMT enzymes with knockdowns and pharmacological inhibitors provide further support for active promoter demethylation with consequential downstream changes in gene expression (Nelson et al, 2008;Noh et al, 2005;Sharma et al, 2008). Currently, this accumulating evidence of active demethylation of CpG dinucleotides as a direct consequence of neuronal activity and cellular signaling in post-mitotic neurons (Chen et al, 2003;Martinowich et al, 2003;Miller and Sweatt, 2007;Ma et al, 2009) has yet to be reconciled with a specific enzymatic mechanism.…”

“…Demethylation induced by membrane depolarization is evident from studies examining the Bdnf and Reln promoters (Chen et al, 2003;Martinowich et al, 2003;Ma et al, 2009). In the earliest such investigations conducted in primary cortical neuron cultures, KCl-induced membrane depolarization was associated with demethylation of a Bdnf promoter and induction of Bdnf mRNA expression (Chen et al, 2003;Martinowich et al, 2003).…”

“…Lee et al (2008) show that increased gene expression in the context of membrane depolarization is associated with changes in DNA methylation, manifesting both increases and decreases at alternate sites along the promoter of the NR2B receptor with consequent altered binding of MeCP2 to these sites. Membrane depolarization is also capable of focusing the deamination/ base-excision demethylating mechanism to promoters with mCpG sites and this is mediated by enzymes of the Gadd45 family of proteins (Ma et al, 2009). Activity-induced demethylation may be one reason why CpG islands containing active gene promoters are predominantly hypo-methylated (Schmitz et al, 2009).…”