m6A: a key player in oligodendrocyte formation and CNS myelination

                   The central dogma of biology, DNA to RNA to Protein, is a concept that has been ingrained into our minds since the moment that we first open a biology textbook. However, many who continue within the biology side of the STEM world come to realize that it’s much more complicated than that. To properly express a gene, many steps must occur correctly and precisely for that gene to function properly and even partake in larger biological systems. There are key players, modulators, present in the development stages of these genes that determine their success or failure.

    A research study conducted in 2018 by Dr. Michaela Frye investigates the regulation of gene expression during developmental stages based on various RNA modifications. (1) Some of these modifications include polyadenylation on the ends of RNA, base isomerization, and methylation on bases and ribose sugars. Due to a high prevalence of m6A within mammalian cells, ranging from 20-40% of present RNA modifications, they posses a large influence on the biological function of the cells. Within m6A are two subunits, METTL3 and METTL14, that determine the specific effect of m6A on gene expression. In cases where cancer cells are present, the overexpression of these subunits causes an increase in cell proliferation and encourages an inhibition of cell differentiation. While m6A is essential to modulate translation of RNA sequences for cell differentiation, the mechanisms underlying its effect on gene expression in various diseases were left for future studies, including that of Dr. Huan Xu.

    During their study, they characterize the METTL14 subunit as a key player in the development of oligodendrocytes which allow for the myelination of the central nervous system (CNS). An inhibition of METTL14 specific to oligodendrocyte formation led to decreased levels of oligodendrocytes during in vitro testing which also led to a “hypomyelination” in the CNS. The scientists concluded that proper function of the METTL14 subunit within the m6A modification is crucial for development of oligodendrocytes post-mitosis. Furthermore, a lack of METTL14 function can cause RNA transcript slicing which can cause a myriad of neurological diseases due to demyelination.

    Ultimately, both studies serve as a foundation to investigate the mechanisms underlying the m6A modulation and its effects on gene expression within cells. Dr. Xu’s work specifies m6A’s neurological influences on myelination and allow for future researchers to explore remedies to ease neurological diseases caused by hypomyelination.

 

References:

 

1.     Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science. 2018 Sep 28;361(6409):1346-1349. doi: 10.1126/science.aau1646. PMID: 30262497; PMCID: PMC6436390.

2. Xu H, Dzhashiashvili Y, Shah A, Kunjamma RB, Weng YL, Elbaz B, Fei Q, Jones JS, Li YI, Zhuang X, Ming GL, He C, Popko B. m6A mRNA Methylation Is Essential for Oligodendrocyte Maturation and CNS Myelination. Neuron. 2020 Jan 22;105(2):293-309.e5. doi: 10.1016/j.neuron.2019.12.013. Epub 2019 Dec 31. PMID: 31901304; PMCID: PMC7137581.