Controversial Roles of Fat Mass and Obesity-Associated Protein in Epitranscriptome
- 1. Department of Biochemistry and Molecular Biology, Saint Louis University Medical School, USA
CITATION
Chang YH, Doisy EA (2018) Controversial Roles of Fat Mass and Obesity-Associated Protein in Epitranscriptome. JSM Biochem Mol Biol 5(1): 1033.
ABBREVIATIONS
FTO: Fat Mass and Obesity-Associated Protein; m6A: N6 methyladenosine; RMBase (RNA modification base (http:// mirlab.sysu.edu.cn/rmbase/); METTL3: methyltransferases-like 3; METTL14: methyltransferases-like 14; WTAP: Wilm’s Tumor Associated Protein; RMB15/15B: RNA Binding Motif Protein 15/15B; ALKBH5: AlkB Homolog 5; m7G: N7-methylguanosine; m6Am: N6,2’-O-dimethyladenosine; MeRIP: Methylated RNA Immunoprecipitation; MiCLIP: m6A Individual-Nucleotide Resolution Cross-Linking and Immunoprecipitation.
EDITORIAL
The discovery of fat mass and obesity-associated protein (FTO) as a demethylase of N6-methyladenosine (m6A) RNA modification, together with findings from two independent reports of transcriptome-wide m6A mapping, renewed interest in the regulatory influences of RNA modifications on mRNA function [1-3]. The term “epitranscriptome” was coined in 2012 to define posttranscriptional modifications in RNA [2]. Since then, rapid progress has been made in characterizing a multitude of RNA modifications, including the m6A RNA modification [4]. Currently, RNA modification (RMBase) base at http://mirlab. sysu.edu.cn/rmbase/ contains over 62,000 m6A peaks in over 10,000 mouse genes and over 118,000 m6A peaks in over 12,000 human genes [5]. Recent research has unveiled key characteristics of m6A modifications, including their underlying mechanisms and physical health consequences. For instance, methyltransferases-like 3 (METTL3) were identified as m6A writers that form a heterodimer methyltransferases-like 14 (METTL14) to catalyze m6A methylation with the support of Wilm’s tumor–associated protein (WTAP) and RNA binding motif protein 15/15B (RBM15/15B) [4]. Moreover, both FTO and AlkB homolog 5 (ALKBH5) are Fe(II)- and α-ketoglutarate-dependent enzymes that are referred to as m6A erasers, and belong to the AlkB family. FTO is expressed in the nucleus of adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment [6]. In humans, loss-of-function mutations in FTO were associated with severe growth retardation and multiple malformations that resulted in premature death [7]. FTO may regulate dopaminergic signaling in the brain and mRNA splicing of adipogenetic regulatory factors, thereby playing a critical role in adipogenesis [8]. FTO has also been shown to play an oncogenic role in acute myeloid leukemia [9]. Despite these important and exciting findings regarding FTO’s role in brain development, cancer, and adipogenesis, the precise function of FTO has been the subject of debate.
Mauer et al. [10], recently found that FTO is approximately 100-times more active against m6Am when presented in its natural context adjacent to the N7-methylguanosine (m7G) cap. Mauer et al., further demonstrated that the level of N6,2’-O dimethyladenosine (m6Am) in FTO knockout cells increased significantly with no detectable increase in m6A, and that expression of a FTO located in the cytoplasm caused a reduction in m6Am with no effect on m6A. Taken together, Mauer et al., revealed that FTO acts as an eraser for m6Am and plays a key role in mRNA stability [10]. In light of these findings, some argue that m6A may have been the incorrect substrate for FTO, given that FTO did not show a preference for m6A at its physiological consensus site and has a relatively low catalytic rate toward m6A relative to other enzymes in its class. To ascertain the accuracy of this claim, it is critical to discuss several additional key aspects of the present m6A modification literature. First, though FTO did not demonstrate preference at its physiological consensus site, FTO does indeed have a very strong preference for m6Am in a specific structural context, particularly when m7G and triphosphate linkers are available to facilitate FTO’s demethylation of m6Am [10]. Second, the catalytic rate of FTO for m6Am is much higher than for m6A in vitro [10]. Third, in a study of FTO in acute myeloid leukemia, a ∼20% increase in m6A was seen upon FTO depletion [9], possibly supporting the idea that FTO is indeed an m6A demethylase. It is important to note that METTL14 mRNA levels also increased 25% in FTO-depleted acute myeloid leukemia cells. Some have suggested that increases in m6A could to be related to the loss of FTO function caused by increased levels of m6A-writer complexes. This hypothesis requires further examination. METTL14 is catalytically inactive, only playing a supportive role for the transferase activity of METTL3. Thus, increases in METTL14 levels may not necessarily result in the increase of m6A writer complexes. Finally, MeRIP Seq method was initially used for transcriptome-wide m6A mapping. One major problem of the MeRIP-Sep approach is that it cannot readily distinguish between m6A and m6Am, given that both react with m6A-specific antibodies. This discovery has led to an overall preference for m6Am as a substrate for FTO in vivo, a preference that is reliant on the development of high-resolution mapping methods such as miCLIP [11,12]. Recently, Hong et al., has developed an antibody-independent m6A mapping method at single-nucleotide resolution. It would be interesting to compare the data obtained from this new method with those from miCLIP. Following further research using improved research tools, we will hopefully have better understanding of the function of FTO in vivo and its exact pathological roles in many important diseases.
