Epigenetic mechanisms in neurogenesis

Abstract

In the embryonic and adult brain, neural stem cells proliferate and give rise to neurons and glia through highly regulated processes. Epigenetic mechanisms - including DNA and histone modifications, as well as regulation by non-coding RNAs - have pivotal roles in different stages of neurogenesis. Aberrant epigenetic regulation also contributes to the pathogenesis of various brain disorders. Here, we review recent advances in our understanding of epigenetic regulation in neurogenesis and its dysregulation in brain disorders, including discussion of newly identified DNA cytosine modifications. We also briefly cover the emerging field of epitranscriptomics, which involves modifications of mRNAs and long non-coding RNAs.

Figure 1. Embryonic and adult neurogenesis

a | During embryonic neurogenesis in mice, neuroepithelial cells are activated around embryonic day 8 (E8) and develop into radial glial cells (RGCs) around E14. RGCs can either give rise to neurons directly or generate intermediate progenitor cells (IPCs), which in turn produce neurons. Later in development, RGCs also generate astrocytes and oligodendrocytes. b | Radial glia-like neural stem cells (RGLs) in the subventricular zone (SVZ) generate transient amplifying IPCs, which produce neuroblasts that migrate through the rostral migratory stream and become interneurons in the olfactory bulb. RGLs also produce oligodendrocytes. c | In the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, activation of quiescent RGLs gives rise to IPCs, which in turn produce neuroblasts that migrate along blood vessels and differentiate into dentate granule neurons. In addition, RGLs can give rise to astroglia in the adult dentate gyrus, and actively suppress an oligodendrocyte fate.

Figure 2. Major forms of epigenetic modifications

a | Schematic illustration of chromatin organization in the nucleus. DNA is packaged into a highly ordered chromatin structure in eukaryotes by wrapping around an octamer of histone proteins, consisting of two copies of histone variants. b | DNA can be dynamically modified. Cytosines can be methylated by DNA methyltransferases (DNMTs) to 5-methylcytosine (5mC), which in turn can be oxidized to become 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) proteins. 5hmC can be further oxidized by TET proteins to become 5-formylcytosine (5fC) and then 5-carboxylcytosine (5caC), or deaminated by activation-induced cytidine deaminase (AID) or apolipoprotein B mRNA-editing enzyme catalytic polypeptides (APOBECs) to become 5-hydroxymethyluracil (5hmU). 5fC, 5caC and 5hmU can be excised by thymine DNA glycosylase (TDG) to generate an abasic site, which can be converted back to a cytosine by the base excision repair (BER) pathway.c | Histone proteins can be modified in diverse ways. Various forms of histone modifications, including histone lysine and arginine methylation, lysine acetylation, ubiquitylation, sumoylation, serine and threonine phosphorylation, and proline isomerization, are indicated. Prevalent histone modifications that regulate gene expression are also listed. Cit, citrulline; DUBs, deubiquitylating enzymes; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; HATs, histone acetyltransferases; HDACs, histone deacetylases; KDMs, lysine demethylases; KMTs, lysine methyltransferases; PADI4, peptidyl arginine deiminase type 4; PRMTs, protein arginine methyltransferases; SENPs, sentrin-specific proteases.