Emerging Role of m6 A Methylome in Brain Development: Implications for Neurological Disorders and Potential Treatment

Published on May 19, 2021in Frontiers in Cell and Developmental Biology5.201
· DOI :10.3389/FCELL.2021.656849
Godwin Sokpor1
Estimated H-index: 1
(RUB: Ruhr University Bochum),
Yuanbin Xie (HMU: Hainan Medical University)+ 1 AuthorsTran Tuoc16
Estimated H-index: 16
(RUB: Ruhr University Bochum)
Dynamic modification of RNA affords proximal regulation of gene expression triggered by non-genomic or environmental changes. One such epitranscriptomic alteration in RNA metabolism is the installation of a methyl group on adenosine (m6A) known to be the most prevalent modified state of mRNA in the mammalian cell. The methylation machinery responsible for the dynamic deposition and recognition of m6A on mRNA is composed of subunits that play specific roles, including reading, writing and erasing of m6A marks on mRNA to influence gene expression. As a result, peculiar cellular perturbations have been linked to dysregulation of components of the mRNA methylation machinery or its cofactors. It is increasingly clear that neural tissues/cells, especially in the brain, make the most of m6A modification in maintaining normal morphology and function. Neurons in particular display dynamic distribution of m6A marks during development and in adulthood. Interestingly, such dynamic m6A patterns are responsive to external cues and experience. Specific disturbances in the neural m6A landscape lead to anomalous phenotypes, including aberrant stem/progenitor cell proliferation and differentiation, defective cell fate choices, and abnormal synaptogenesis. Such m6A-linked neural perturbations may singularly or together have implications for syndromic or non-syndromic neurological diseases, given that most RNAs in the brain are enriched with m6A tags. Here, we review the current perspectives on the m6A machinery and function, its role in brain development and possible association with brain disorders, and the prospects of applying the CRISPR-dCas13b system to obviate m6A-related neurological anomalies.
#1Pauline Antonie Ulmke (GAU: University of Göttingen)H-Index: 2
#2Yuanbin Xie (GAU: University of Göttingen)H-Index: 2
Last. Tran Tuoc (GAU: University of Göttingen)H-Index: 16
view all 12 authors...
Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N6-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development. However, m6A methylation impacts not only RNA stability, but also other RNA metabolism processes. How RNA decay contribute to brain development is largely unknown. Here, we show that Exosc10, an RNA exonuclease subunit of the RNA exosome complex, ...
1 CitationsSource
#1Andrew M Shafik (Emory University)H-Index: 3
#2Feiran Zhang (Emory University)H-Index: 12
Last. Peng Jin (Emory University)H-Index: 72
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BACKGROUND N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain. RESULTS We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue...
2 CitationsSource
#1Cassandra Kontur (Yale University)H-Index: 2
#2Minsun JeongH-Index: 2
Last. Antonio J. Giraldez (Yale University)H-Index: 36
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Summary During the maternal-to-zygotic transition (MZT), multiple mechanisms precisely control massive decay of maternal mRNAs. N6-methyladenosine (m6A) is known to regulate mRNA decay, yet how this modification promotes maternal transcript degradation remains unclear. Here, we find that m6A promotes maternal mRNA deadenylation. Yet, genetic loss of m6A readers Ythdf2 and Ythdf3 did not impact global maternal mRNA clearance, zygotic genome activation, or the onset of gastrulation, challenging th...
2 CitationsSource
#1Lior Lasman (Weizmann Institute of Science)H-Index: 6
#2Vladislav Krupalnik (Weizmann Institute of Science)H-Index: 12
Last. Jacob H. Hanna (Weizmann Institute of Science)H-Index: 54
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The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m6A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their seq...
21 CitationsSource
#1Tingfu Du (Academy of Medical Sciences, United Kingdom)H-Index: 1
#2Guoxiang Li (Academy of Medical Sciences, United Kingdom)H-Index: 1
Last. Kaili Ma (Academy of Medical Sciences, United Kingdom)H-Index: 1
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Abstract N6-methyladenosine (m6A) RNA methylation is one of the most abundant internal modifications on mRNAs and highly enriched within the brain. The demethylation of m6A is regulated by demethylases including fat-mass and obesity-associated protein (FTO) and AlkB homolog 5 (Alkbh5). FTO has been shown to play an important role in the brain, but little is known about the expression pattern and role of Alkbh5. Here, we investigated the expression profile of Alkbh5 in the developing mouse brain ...
5 CitationsSource
#1Longbin ZhangH-Index: 2
#2Kunzhao DuH-Index: 1
Last. Tao Sun (Huaqiao University)H-Index: 6
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N6-methyladenosine (m6A)-mediated epitranscriptomic regulation is critical for various physiological processes. Genetic studies demonstrate that proper m6A-methylation is required for mouse brain development and function. Revealing landscapes of m6A-methylation in the cerebral cortex at different developmental stages will help to understand the biological meaning of epitranscriptomic regulation. Here, we depict the temporal-specific m6A-methylation status in mouse embryonic and postnatal cortice...
#1Anil K. Chokkalla (UW: University of Wisconsin-Madison)H-Index: 5
#2Suresh L. Mehta (UW: University of Wisconsin-Madison)H-Index: 23
Last. Raghu Vemuganti (UW: University of Wisconsin-Madison)H-Index: 49
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Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N6 position generates N6-methyladenosine (m...
2 CitationsSource
RNA modifications termed epitranscriptomics represent an additional layer of gene regulation similar to epigenetic mechanisms operating on DNA. The dynamic nature and the increasing number of RNA modifications offer new opportunities for a rapid fine-tuning of gene expression in response to specific environmental cues. In cooperation with a diverse and versatile set of effector proteins that "recognize" them, these RNA modifications have the ability to mediate and control diverse fundamental cel...
#1He Huang (UQ: University of Queensland)H-Index: 2
#2Judith Camats-Perna (UQ: University of Queensland)H-Index: 3
Last. Jocelyn Widagdo (UQ: University of Queensland)H-Index: 13
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Abstract Cognitive impairment in Alzheimer’s disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, N6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is pe...
#1Rongrong Huang (SEU: Southeast University)H-Index: 9
#2Yuan Zhang (SEU: Southeast University)H-Index: 19
Last. Honghong Yao (SEU: Southeast University)H-Index: 34
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Abstract Background N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events in physiological and pathological processes. However, precisely how m6A methylation is involved in major depressive disorder (MDD) is not fully understood. Methods Circular RNA STAG1 (circSTAG1) was screened from the hippocampus of chronic unpredictable stress (CUS) mice using high-throughput RNA sequencing. Microinjection of circSTAG1 ...
22 CitationsSource
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