The Epigenome in Neurodevelopmental Disorders

Abstract

Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted.

Keywords: DNA methylation; chromatin remodeling; corticogenesis; epigenetics; histone modification; neuropsychiatry; non-coding RNAs.

FIGURE 1

Critical milestones of human corticogenesis and associated NDDs. The human cerebral cortex begins to form by symmetric division of neuroepithelial cells (NECs, bright gray) in the first trimester, which elongate in shape to convert to radial glial cells (RGCs, dark gray). RGCs increase in number, asymmetrically divide and convert to outer radial glial cells (oRGCs) also known as basal RGCs, or give rise to neuronal intermediate progenitor cells (nIPCs), again by asymmetric division. The latter further divide symmetrically to give rise to young excitatory principal neurons (pink), which migrate from the subventricular zone (SVZ) toward the forming cortical plate (CP). Inhibitory interneurons (brown) invade the developing neocortex along the marginal zone (MZ) or the subplate (SP) and SVZ, before they switch to radial migration to enter the cortical plate. Increased progenitor and neuronal numbers as well as rapidly expanding neuronal networks contribute to physical stress, forming the main gyri at the end of the second trimester. At later stages of corticogenesis, intercellular connections begin to form, for which morphological differentiation and defined setting of neuronal proportions are necessary. Failures of corticogenesis are suggested to contribute to various NDDs with respect to the given time point and affected process, which is depicted on the bottom for different examples of diseases. CP = cortical plate; iSVZ = inner subventricular zone; IZ = intermediate zone; MZ = marginal zone; NE = neuroepithelium; oSVZ = outer subventricular zone; SP = subplate; VZ = ventricular zone.

FIGURE 2

Examples of NDDs involving epigenetic key players and affected processes during corticogenesis assumed to contribute to the respective diseases. Increased progenitor proliferation and decreased neurogenesis due to dysregulated function of WNT can be traced back to aberrant activity of PCR2, KMT2C, KDM5B or ASHL1 in ASD. In individuals affected by Down syndrome, miR125b and MECP2 are associated to altered CDKN2A expression and glial proliferation. For patients with Wolf-Hirschhorn syndrome neuronal progenitor proliferation is disturbed by aberrant activity of LSD1/KDM1A and HDAC, both targeting the transcription factor TFII-I, as well as dysregulated function of NSD2, which is influencing the expression of NKX2.5. In case of ICF syndrome, associated mutations in DNMT3B are resulting in hypomethylated genes essential for neuronal migration (LHX2, ROBO1, CXCR4, IFRD2, DTX4, ENC1, JARID2, SEMA3B, and ITM2). Additionally, patients with Weaver syndrome are characterized by neuronal migration defects, due to haploinsufficiency of EZH2, disturbing PRC2 activity, and mutations in NSD1, impairing proper establishment of histone marks. At the level of interneuron migration, different miRNAs are regulating this pivotal step of corticogenesis. For example, downregulation of miR-34a is affecting NEUROG2 expression, which is essential for neuronal migration. Mutations in UBE3A and dysregulated expression of MECP2 and SETDB1 are linked to susceptibility of Angelman syndrome, which is also characterized by deficits in axonal branching, spine formation and synapse generation. In individuals with Kleefstra syndrome, dysregulated interhemispheric connections are reported as potential result of mutations in EHMT1, leading to disturbed interaction with EHMT2 or EZH2 and changes in expression of genes coding for epigenetic regulators, such as MML3, SMARCB1, NR1I3, or MBD5. Deficits in ATRX-MECP2 interaction, subsequent aberrations in H3K9me3 marks and resulting improper neuronal proportions in different cortical and subcortical areas are depicted for ATR-X syndrome.