Gene Expression Dysregulation in Central Nervous System (CNS)

Introduction of Gene Expression Dysregulation

Gene expression regulation is essential for the development and function of the mammalian central nervous system (CNS). A series of cell types, such as neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells, can be generated through strict control of cell proliferation, migration, and differentiation. Recent research has shown that genome topology and relocation of gene loci within the nucleus are key factors for transcriptional regulation. And there are also multiple factors that influence transcription, such as nucleosome remodeling, non-coding RNAs, epigenetic modifications of DNA and histones, as well as region relocation to specific nuclear compartments. Folding the genome into sub-TAD and TAD compartments would limit the contacts between genes and their enhancers and co-regulated genes, and finally plays an important role in gene expression regulation.

Fig.1 Neuronal differentiation is marked by genome architecture changes. (Brookes, 2019)

Mechanisms of Neurological Disorders by Alteration of Genome Topology

Disruption of chromosome organization is associated with the transcriptional dysregulation observed in many neurological disorders.

• Organizer gene mutation - The mutation of organizer genes results in the loss of some important proteins and thereby has a huge impact on downstream gene expression.
• TAD boundary mutation - The mutations in TAD boundaries result in neighboring TADs merging and induce inappropriate gene activation.
• Enhancer mutation - The enhancer mutations would prevent sub-TAD interactions to abrogate gene activation.

Fig.2 Mechanisms of disease caused by alteration of genome topology. (Brookes 2019)

Gene Expression Dysregulation in Cockayne Syndrome

Cockayne syndrome (CS) is an autosomal-recessive, multisystem disorder with severe neurological symptoms, including growth failure, photosensitivity, developmental abnormalities, and degeneration of organ systems. Most of the CS patients carry mutations in Cockayne syndrome group B (CSB), which plays an important role in transcription-coupled repair. Even without the DNA damage, CSB can affect the expression of thousands of genes, especially neuronal genes. According to the experiments using human and mouse cell models, as well as brain tissue from CS patients, we have found that the absence of CSB can lead to defects in the gene expression program required for neuronal differentiation. In conclusion, the main cause of neurological symptoms in CS is the dysregulation of gene regulatory networks rather than DNA repair defects.

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References

1. Brookes, E; Riccio, A. Location, location, location: Nuclear structure regulates gene expression in neurons. Current opinion in neurobiology. 2019, 59: 16-25.
2. Wang, Y; et al. Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease. Proceedings of the National Academy of Sciences. 2014, 111(40): 14454-14459.