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Review
. 2020 Nov;53(11):551-564.
doi: 10.5483/BMBRep.2020.53.11.204.

Epitranscriptomic regulation of transcriptome plasticity in development and diseases of the brain

Chan-Woo Park  1 , Sung-Min Lee  1 , Ki-Jun Yoon  1
Affiliations
Review

Epitranscriptomic regulation of transcriptome plasticity in development and diseases of the brain

Chan-Woo Park et al. BMB Rep. 2020 Nov.

Abstract

Proper development of the nervous system is critical for its function, and deficits in neural development have been implicated in many brain disorders. A precise and predictable developmental schedule requires highly coordinated gene expression programs that orchestrate the dynamics of the developing brain. Especially, recent discoveries have been showing that various mRNA chemical modifications can affect RNA metabolism including decay, transport, splicing, and translation in cell typeand tissue-specific manner, leading to the emergence of the field of epitranscriptomics. Moreover, accumulating evidences showed that certain types of RNA modifications are predominantly found in the developing brain and their dysregulation disrupts not only the developmental processes, but also neuronal activities, suggesting that epitranscriptomic mechanisms play critical post-transcriptional regulatory roles in development of the brain and etiology of brain disorders. Here, we review recent advances in our understanding of molecular regulation on transcriptome plasticity by RNA modifications in neurodevelopment and how alterations in these RNA regulatory programs lead to human brain disorders. [BMB Reports 2020; 53(11): 551-564].

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflicting interests.

Figures

Fig. 1
Fig. 1
The Epitranscriptomic machinery and its regulatory function in eukaryotes. Eukaryotic RNA modifications, including m6A, Nm, m5C and ψ (depicted clock-wisely in this board from top left) can be installed, read and removed by specialized proteins known as writer (marked with a keyboard), reader (marked with a magnifier) and eraser proteins (marked with a rubber), respectively. The dyna-mic alteration of transcriptome plasticity conferred by each of RNA modifications includes RNA degradation, splicing, nuclear export, translation, as well as the processing of non-coding RNAs. Each RNA modification is illustrated in a pin with different colors: m6A - red, Nm - yellow, m5C - green, and ψ - blue, respectively.
Fig. 2
Fig. 2
The roles of epitranscriptome in neurodevelopment. During the embryonic and postnatal development, RNA modifications play important roles in regulation of transcriptome plasticity, by which different developmental programs of the CNS, such as embryonic neurogenesis, gliogenesis, cerebellar development, adult neurogenesis, neuronal maturation, and synapse formation are precisely progressed. Bottom panels comprehensively summarize the physiological functions of m6A, Nm, and m5C in neurodevelopment revealed by of loss- and/or gain-of-function studies about related epitranscriptomic machinery. RGC, radial glial cell; IPC, intermediate progenitor cell; CLN, cortical layer neuron; AST, astrocyte; ODC, oligodendrocyte; EGL, external granular layer; IGL, inner granule cell layer; PCL, Purkinje cell layer; aNSC, adult neural stem cell; Mm, Mus musculus; Dr, Danio rerio.
Fig. 3
Fig. 3
Epitranscriptomic regulation in major brain disorders. Epitranscriptomic RNA modifications are involved in multiple types of brain disorders. Human genetic analysis and animal model studies revealed that various RNA modifications and their regulatory machineries have critical roles in etiology of neurogenerative disorders, intellectual disability, mental disorders, and brain cancers. ADHD, attention deficit hyperactivity disorder; MLASA, mitochondrial myopathy, lactic acidosis, and sideroblastic anemia; XLMR, X-linked mental retardation; m6A, N6-methyladenosine; ψ, pseudouridine; m5C, 5-methylcytosine; Nm, 2’-O-methylation.
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