The role of histone modifications: from neurodevelopment to neurodiseases

Abstract

Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation and organ development through spatial and temporal gene regulation. Neurogenesis is a sophisticated and complex process by which neural stem cells differentiate into specialized brain cell types at specific times and regions of the brain. A growing body of evidence suggests that epigenetic mechanisms, such as histone modifications, allow the fine-tuning and coordination of spatiotemporal gene expressions during neurogenesis. Aberrant histone modifications contribute to the development of neurodegenerative and neuropsychiatric diseases. Herein, recent progress in understanding histone modifications in regulating embryonic and adult neurogenesis is comprehensively reviewed. The histone modifications implicated in neurodegenerative and neuropsychiatric diseases are also covered, and future directions in this area are provided.

Fig. 1

Embryonic neurogenesis. Neuroepithelial cells (NECs) give rise to radial glial cells (RGCs). RGCs divide asymmetrically to produce neuron and neuroglial cells (astrocyte and oligodendrocyte) through neurogenic intermediate progenitor cell (nIPC) and oligogenic intermediate progenitor cell (oIPC), respectively. CP cortical plate, IZ intermediate zone, SVZ subventricular zone, VZ ventricular zone

Fig. 2

Adult neurogenesis. a Adult neurogenesis in the olfactory bulb (SVZ) and hippocampus (SGZ). b The process of adult neurogenesis in the olfactory bulb requires a series of steps. RGL activation can generate IPCs that proliferate and differentiate into neuroblast. Some of neuroblasts migrate through the rostal migratory stream (RMS) and become mature and integrate into mature granule or periglomerular neurons in the olfactory bulb (OB). c The SGZ niche is composed of RGL, IPC, neuroblast, and granule neuron. Adult neurogenesis in the SGZ undergoes a process similar to that in the SVZ. ML molecular layer, GCL granule cell layer

Fig. 3

Histone modifications during embryonic neurogenesis. Histone modifications (e.g., acetylation, methylation, crotonylation, and serotonylation) and other epigenetic regulators (e.g., histone variants) are involved in embryonic neurogenesis. Various HATs (p300/CBP, KAT6B, and KAT8) and HDACs (HDAC1-4) are involved in embryonic neural development by regulating gene expression. Changes in histone methylation by writers (SETD1A/1B, SETDB1, EZH2, SETD5, DOT1L, and PRMT6) or erasers (LSD1, KDM5C, PHF2, and KDM6B) control gene expression, promoting embryonic neurogenesis. Other histone modifications (crotonylation and serotonylation) and histone variants (H2A.X, macroH2A1.2, and H3.3) are involved in embryonic neurogenesis

Fig. 4

Histone modifications during adult neurogenesis. In SVZ, KAT6 and HDAC1/2 regulate neurogenesis. HMTs (MLL1 and EZH2) and HDMs (KDM5B and KDM6B) regulates gene expression related to neurogenesis. In SGZ, HAT (p300), HDACs (HDAC1/2 and SIRT6), and HMTs (SUV39H1/2 and EZH2) promote neural differentiation by regulating gene expression

Fig. 5

Dysregulation of histone-modifying enzymes and histone modifications in Alzheimer’s disease (AD). Histone acetylation such as H3K9ac and H3K27ac is globally increased due to the increase of CBP/p300 expression. In contrast, acetylation of H3K12 is reduced by the increased HDACs (e.g., HDAC2). In AD, HMTs responsible for H3K4me3 and H3K9me2 are overexpressed: SETD1A/1B and MLL3/4 for H3K4me3, GLP/G9a (EHMT1/2) for H3K9me2. These affect the levels of H3K4me3 and H3K9me2 on a global and gene-specific level, thereby altering gene expression. H2A ubiquitination (H2AK119ub by PRC1), H3 lactylation (H3K12la by p300), H2A.X phosphorylation (H2A.XS139p) are increased in AD. SIRT1 downregulation in AD leads to the elevated Aβ levels and their aggregation. HDAC6 increase in AD stimulates tau phosphorylation, thereby facilitating tau aggregation

Fig. 6

Dysregulation of histone-modifying enzymes and histone modifications in Parkinson’s disease (PD). Several neurotoxins induce H3 and H4 acetylation together with changing the expression of HATs and HDACs. For example, Paraquat and MPTP increase H3 and H4 acetylation. Dieldrin induces H3K14ac by increasing CBP expression. Rotenone reduces SirT1 expression levels, thereby increasing H3K9ac. Histone methylation is also dysregulated in PD. PD-related neurotoxin such as 6-OHDA reduces H3K4me3 and H3K27me3. Furthermore, H3K4me3 at the SNCA promoter is increased in PD patient

Fig. 7

Effect of α-synuclein overexpression on PD-related gene expression. a Overexpression of wild-type α-synuclein (SNCA^WT) reduces H3 acetylation levels by suppressing p300 expression, resulting in downregulating key genes related to DNA repair. b Mutant α-synuclein (SNCA^MUT) expression induces HDAC2 expression but inhibits Tip60 expression, leading to the decrease of H3K16ac and H4K12ac at the neuroplasticity related genes. c Wild-type α-synuclein overexpression increases G9a expression, which negatively regulated SNARE complex gene expression (i.e., LICAM and SNAP25) by depositing H3K9me1/2

Fig. 8

Dysregulation of histone-modifying enzymes and histone modifications in schizophrenia (SZ). Increase of repressive histone marks (e.g, H3 deacetylation by HDAC1, decrease of H3K4me3 by loss of MLL1 or SETD1A mutation, and increase of H3K27me3) suppresses GAD1 expression. Increase in H2A.Z acetylation, H3K9me3, and H3R17me is observed in SZ

Fig. 9

Dysregulation of histone-modifying enzymes and histone modifications in major depressive disorder (MDD). Neural circuit (cortical-striatal-limbic circuit) is structurally functionally disconnected in MDD. Histone modifications in brain regions such as prefrontal cortex (PFC), hippocampus, nucleus accumbens (NAc), and amygdala are various. In general, repressive marks are increased in PFC and hippocampus. In NAc and amygdala, active or repressive histone marks are observed in the promoter regions