Epigenetic choreographers of neurogenesis in the adult mammalian brain

Abstract

Epigenetic mechanisms regulate cell differentiation during embryonic development and also serve as important interfaces between genes and the environment in adulthood. Neurogenesis in adults, which generates functional neural cell types from adult neural stem cells, is dynamically regulated by both intrinsic state-specific cell differentiation cues and extrinsic neural niche signals. Epigenetic regulation by DNA and histone modifiers, non-coding RNAs and other self-sustained mechanisms can lead to relatively long-lasting biological effects and maintain functional neurogenesis throughout life in discrete regions of the mammalian brain. Here, we review recent evidence that epigenetic mechanisms carry out diverse roles in regulating specific aspects of adult neurogenesis and highlight the implications of such epigenetic regulation for neural plasticity and disorders.

Figure 1

Basic modes of epigenetic regulation implicated in adult neurogenesis. (a) To initiate epigenetic processes, extracellular and intracellular signals may trigger epigenetic ‘perpetuators’ that form self-sustaining feedback loops or intrinsically produce long-lasting cellular effects in the absence of the initial trigger stimuli. Typical mechanisms by which this process occurs include transcription regulator and non-coding RNA–mediated feedback pathways, DNA methylation with associated methyl-binding proteins (MBDs), and histone H3K27 methylation with associated PcG (polycomb group) and TrxG (trithorax group) complexes. (b) DNA modifications. DNA methyltransferases (DNMTs) catalyze DNA methylation, whereas the pathway leading to DNA demethylation might include 5-methylcytosine (5mC) hydroxylase TET (ten-eleven translocation-1) proteins and DNA excision repair enzymes that are regulated by Gadd45 (growth arrest and DNA-damage-inducible) family proteins. (c) Histone modifications. Specific amino acid residues of histone N-terminal tails can be reversibly modified with a variety of ‘tags’ including acetylation (ac), phosphorylation (p), methylation (me), ubiquitination (ub), SUMOylation (su) and isomerization (iso). The varying turnover rates and biological interpreters of these modifications might execute different cellular functions for epigenetic regulation. C, cytosine; 5mC, 5-methylcytosines; 5hmC, 5-hydroxymethylcytosine; BER, base-excision repair; NER, nucleotide-excision repair; K, lysine; S, serine; T, threonine; R, arginine; P, proline; KAT, lysine acetyltransferase; HDAC, histone deacetylase; KMT, lysine methyltransferase; KDM, lysine deacetylase; PRMT, protein arginine methyltransferase; PADI4, peptidyl arginine deiminase type IV; JMJD6, Fe(II) and 2-oxoglutarate–dependent dioxygenase Jumonji domain-6 protein; DUB, deubiquitinase; SENP, sentrin-specific protease.

Figure 2

Classic and emerging technologies for epigenetic analysis of adult neurogenesis. During adult neurogenesis in the SGZ, neural stem cells (nestin⁺ and GFAP⁺) differentiate into immediate neural progenitors (Trb2⁺) and then newborn neurons (DCX⁺ and PSA-NCAM⁺) and finally into mature new neurons (NeuN⁺). To profile gene-specific epigenetic modifications, homogeneous target cell populations should be isolated and purified using laser capture microdissection or various prospective cell-labeling strategies. DNA methylation analysis can then be performed using bisulfite sequencing or methylation-sensitive restriction-based approaches. ChIP can be used to profile both DNA and histone modifications. The emerging technology of next-generation sequencing platforms allows rapid, genome-scale, high-resolution mapping of both DNA and histone modifications. RNA expression profiling may validate and further reveal new biological signatures for activated or repressed chromatin states.

Figure 3

Major epigenetic regulators of adult neurogenesis. (a) Current understanding of epigenetic regulation of adult neurogenesis in SGZ and SVZ. Adult neural progenitors undergo proliferation and generate neuroblasts that can further differentiate into mature, functional neurons. Neurogenesis can be regulated by intrinsic epigenetic mechanisms within the neuronal lineage of adult neural progenitors and extrinsically by nearby niche signaling cells, such as mature neurons, astrocytes and endothelial cells. During the stages of adult neurogenesis, diverse epigenetic mechanisms use common or different sets of molecules, including DNMT, PcG and TrxG, HDAC, MBD and Gadd45 family proteins, in either adult neural progenitors and their progeny or nearby niche cells to choreograph cell state transitions in coordination with other internal and external cues. Common molecules, such as HDACs, are likely to have different partners or binding sites depending on the differentiation stage during neurogenesis. Prototypical cell stages are shown to reflect identified epigenetic regulators for both SVZ and SGZ adult neurogenesis. (b) During early stages of adult hippocampal neurogenesis in the SGZ, L1 transcription is regulated by the transcription factors Sox2 and TCF to maintain the long-term silencing state, even during cell division. In response to external stimuli such as neuronal activity or Wnt signaling, the balance of co-repressor and co-activator in the L1 promoter is tipped to activation of L1 expression, driving its genomic retrotransposition. After terminal differentiation, adult neural progenitor–specific expression of Sox2 is downregulated and L1 transcription and retrotransposition are decreased. DNA methylation and MBD-mediated epigenetic mechanisms could act to ensure the long-term silencing of L1 by recruiting transcriptional co-repressors. CoA, co-activator; CoR, co-repressor; DG, dentate gyrus.