Key Points
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ATP-dependent chromatin remodellers and chromatin modifiers can have important roles in specific biological processes, such as brain development and function. Disruption of chromatin regulation can lead to neurodevelopmental and psychiatric diseases.
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Recent exome-sequencing studies of human mental disorders have identified causal mutations in chromatin regulators. Newly uncovered mutations will guide researchers to important mechanistic studies of human mental disorders in the hope of identifying targets for disease treatments and learning more about the development and function of the brain.
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So far, mutations in nine genes encoding seven subunits of SWI/SNF-like BAF chromatin-remodelling complexes have been identified in various mental disorders, including: intellectual disability, Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NBS), Kleefstra's syndrome, non-familial autism spectrum disorder (ASD) and schizophrenia. The essential switch of BAF complex subunits during differentiation of neural progenitors to postmitotic neurons as well as the rate-limiting role of BAF complexes in induced neuron formation indicate that neuronal dendritic morphogenesis and targeting might be a common underlying disease mechanism.
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Recent exome-sequencing studies identified de novo mutations in multiple members of CHD family chromatin remodellers, most notably CHD8, in patients with non-familial autism spectrum disorder (ASD). We speculate that the interplay between CHD8 and the WNT/β-catenin signalling pathway, a major regulator of neurodevelopment, contributes to ASD phenotypes.
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The enhancer of zeste 2 (EZH2) enzyme, a subunit of the Polycomb repressive complex 2 (PRC2), is mutated in numerous cases of Weaver's syndrome. EZH2 has a role in various neural development processes, and its antagonistic role to proteins, such as BAF complexes, on key neural development genes (for example, β-catenin targets) may be important for understanding disease mechanisms.
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Mouse genetic studies showed that histone deacetylase 4 (HDAC4) is involved in learning, memory and long-term synaptic plasticity. This role is potentially the cause of brachydactyly mental retardation syndrome in patients with HDAC4 mutations.
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Interestingly, many of the chromatin regulators mutated in human neurodevelopmental disorders are also mutated in human cancer. This may suggest unanticipated mechanisms of chromatin regulation in human diseases.
Abstract
Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have uncovered mutations in many chromatin regulators. These human genetic studies, along with studies in model organisms, are providing insight into chromatin regulatory mechanisms in neural development and how alterations to these mechanisms can cause cognitive deficits, such as intellectual disability. We discuss several implicated chromatin regulators, including BAF (also known as SWI/SNF) and CHD8 chromatin remodellers, HDAC4 and the Polycomb component EZH2. Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains. We speculate on the contribution of these similar mutations to disparate disorders.
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Change history
09 May 2013
In this article, some of the references citations were incorrectly numbered in the 'Chromatin remodellers' section and in Table 1. This has now been corrected online. The editors apologize for this mistake.
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Acknowledgements
We apologize to colleagues whose work we did not cite owing to lack of space or unintentional oversight. This work was supported by the Howard Hughes Medical Foundation, a grant from the California Institute for Regenerative Medicine and US National Institutes of Health grants NS046789 and CA163915 to G.R.C.
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FURTHER INFORMATION
Supplementary information
Supplementary Table 1
Chromatin regulators mutated in mental disorders (PDF 277 kb)
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Tables of mutations from Box 1 (XLS 100 kb)
Glossary
- Exome sequencing
-
Targeted sequencing of protein-coding regions of the genome (that is, exons). It is a cheaper yet still effective alternative to whole-genome sequencing to identify clinically relevant gene variations that are responsible for both Mendelian and common diseases but does not detect mutations in non-coding regions of the genome
- Glomerulus
-
The glomerulus is a spherical structure located in the olfactory bulb. Each glomerulus is thought to receive input from olfactory receptor neurons (expressing only one type of olfactory receptor). They relay this information into higher brain structure through projection neurons.
- Autosomal dominant disease
-
Refers to a disease arising from mutations on non-sex chromosomes that are genetically dominant.
- Microcephaly
-
Microcephaly is a significantly smaller head measurement. It can be caused by an abnormal brain size due to loss of any number of cell types or brain features and can even be caused by abnormal ventricular spaces or cerebral fluid.
- Haploinsufficiency
-
When the product of one normal allele of a gene is not sufficient to allow the normal function of a gene to be executed. This is another possible cause of genetic dominant diseases.
- Frameshift indel
-
An insertion and/or deletion mutation that changes the reading frame of a protein and creates an altered gene product.
- Dominant-negative
-
Interference with the function of the normal allele of a gene by a mutated allele. This usually occurs when the mutant product can still interact with the same elements as the wild-type product, but block some aspect of its function. This is another possible cause of genetic dominant diseases.
- Corpus callosum
-
A wide flat bundle of neural fibres that connects the left and right cerebral hemispheres and facilitates interhemispheric communication.
- De novo mutations
-
Alterations in genes that are present for the first time in one family member as a result of a mutation in a germ cell (that is, an egg or sperm) of one of the parents or in the fertilized egg itself.
- WNT/β-catenin signalling
-
The binding of WNT ligand to receptor Frizzled leads to a cascade of events allowing for β-catenin (an integral cell–cell adhesion adaptor protein as well as transcriptional co-regulator) stabilization, nuclear translocation and transcriptional activation. The WNT/β-catenin pathway integrates signals from many other pathways, including retinoic acid, FGF, TGFβ and BMP in many different cell types and tissues.
- Single-nucleotide polymorphisms
-
(SNPs). DNA sequence variations that occur when a single nucleotide (A, T, C or G) in the genome or other shared sequence differs between members of a biological species or paired chromosomes in an individual.
- Linker histone
-
The linker histone H1 binds the nucleosome and the entry or exit sites of the DNA, allowing for the formation of higher-order chromatin structures that are thought to lead to chromatin compaction and gene repression.
- Macrocephaly
-
Macrocephaly is a significantly larger than average head circumference measurement. It can be caused by an abnormal brain size due to gain of any number of cell types or brain features and can even be caused by abnormal ventricular spaces or cerebral fluid.
- Polycomb group proteins
-
These conserved proteins form multimeric complexes that exert their functions by modifying chromatin structure and by regulating the deposition and recognition of multiple post-translational histone modifications. Their epigenetic role appears to arise from their ability to propagate a repressive chromatin modification over several kilobases of DNA.
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Ronan, J., Wu, W. & Crabtree, G. From neural development to cognition: unexpected roles for chromatin. Nat Rev Genet 14, 347–359 (2013). https://doi.org/10.1038/nrg3413
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DOI: https://doi.org/10.1038/nrg3413
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Effects of MAP4K inhibition on neurite outgrowth
Molecular Brain (2023)
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Post-transcriptional control of a stemness signature by RNA-binding protein MEX3A regulates murine adult neurogenesis
Nature Communications (2023)
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Transcription and FACT facilitate the restoration of replication-coupled chromatin assembly defects
Scientific Reports (2023)
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Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK
Biophysical Reviews (2023)
