Almén, M. S., Jacobsson, J. A., Moschonis, G., Benedict, C., Chrousos, G. P., Fredriksson, R., & Schiöth, H. B. (2012). Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics, 99(3), 132-137.
A genome wide DNA methylation profile was used to determine which genes were differentially methylated in carriers of the FTO risk allele (rs9939609). They identified 20 different sites associated with obesity. Overall this paper wasn’t extremely helpful for my project but allowed me to understand the characteristics of the FTO gene and how the risk allele can be mediated by epigenetic changes.
Church, C., Moir, L., McMurray, F., Girard, C., Banks, G. T., Teboul, L., … Cox, R. D. (2010). Overexpression of Fto leads to increased food intake and results in obesity. Nature Genetics, 42(12), 1086–1092.
This study shows how overexpression of the FTO gene leads to increases in body and fat mass regardless of whether they were fed a normal or high fat diet. The increased body mass as primarily the result of increased food intake. This paper was useful in that it sparked my interest in how FTO overexpression resulted in increased obesity risk. They also looked at the effects diet had on the resulting phenotype, which I also based my experiment on.
Hess, M. E., Hess, S., Meyer, K. D., Verhagen, L. A., Koch, L., Brönneke, H. S., … & Belgardt, B. F. (2013). The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nature neuroscience, 16(8), 1042-1048.
This paper showed how inactivation of the FTO gene resulted impaired dopamine receptor functions governing the neuronal DA signaling pathway. They compared the genes Drd3, Kcnj6, and Grin1 which are all key regulators of the DA pathway. Results showed that mRNAs had increased m6A methylation and protein expression was attenuated. This paper was extremely important to my experiment as it introduced me to the genes specific to the DA pathway which were affected by epigenetic modifications when FTO expression changed. It also provided me a basis for my experimental design and I ended up basing my methods on the MeRIP-Seq technique they used.
Ishii D, Matsuzawa D, Matsuda S, Tomizawa H, Sutoh C, Shimizu E (2014) Methyl Donor-Deficient Diet during Development Can Affect Fear and Anxiety in Adulthood in C57BL/6J Mice. PLoS ONE 9(8): e105750.
Methyl donors, such as folic acid, methionine, and choline are related to one-carbon metabolism and mediate methylation. This study examines the effects of methyl donor deficiency during a developmental period in fear memory acquisition/extinction and anxiety-like behavior. Results showed that methyl donor deficiency caused mice to have an impaired fear memory acquisition and reduced anxiety-like behavior by decreasing the expression of Dnmt3a, Dnmt3b, Grin2b and Gabar2. This paper mainly introduced me to the idea of methyl donor supplementation and helped me formulate my question to incorporate the effects of diet supplementation on RNA epigenetic changes.
Jia, G., Fu, Y., & He, C. (2013). Reversible RNA adenosine methylation in biological regulation. Trends in Genetics, 29(2), 108-115.
This paper mainly discusses the m6A RNA modification mechanism associated with regulating cell fate decisions. It helped me understand RNA epigenetics and the furthered my understanding of the mechanism associated with m6A. This proved to be helpful when figuring out how the FTO demethylase altered mRNA methylation levels.
McGuinness, D. H., & McGuinness, D. (2014). m 6 a RNA Methylation: The Implications for Health and Disease. Journal of Cancer Science and Clinical Oncology, 1(1), 1.
This paper discussed how m6A modification is a dynamic process and how such modifications can translate into cellular activity. Specifically it suggested how m6A impacted brain systems and was useful for me when I was in the process of relating RNA epigenetics to cellular processes and overall brain functions related to behavior. This helped me tie together key concepts regarding m6A and changes to neuronal pathways in the brain, including DA signaling.
Merkestein M, McTaggart JS, Lee S, Kramer HB, McMurray F, Lafond M, et al. (2014) Changes in Gene Expression Associated with FTO Overexpression in Mice. PLoS ONE 9(5): e97162.
Mice expressing two additional copies of the FTO gene (FTO-4) exhibit increased adiposity and are hyperphagic. FTO is a demethylase and targets m6A modification in RNA, which plays a role in regulating gene expression. This study examines the changes in gene expression that occur in FTO-4 mice and suggest that they up-regulate anabolic pathways and down-regulate catabolic pathways. However, no effect of FTO overexpression on m6A methylation of total mRNA was found. This paper mainly provided inspiration for the idea of upregulating FTO expression by expressing additional alleles of the gene. However, it also showed that different genes were epigenetically modified in different tissue types, suggesting FTO regulates a network of obesity related genes.
Pogribny IP, Karpf AR, James SR, Melnyk S, Han T, et al. (2008) Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet. Brain Res 1237: 25–34.
This paper explained how long term administration of a folate/methyl-deficient diet led to epigenetic changes in the rat brain. This study provided insight on how the availability of methyl donors controls the activity of methyltransferases and demethylases, which inspired me to come up with my specific question.
Wardle, J., Llewellyn, C., Sanderson, S., & Plomin, R. (2009). The FTO gene and measured food intake in children. International journal of obesity, 33(1), 42-45.
The paper discusses how polymorphisms in the FTO gene have been linked to sensitivity to satiety in children and eating behavior. This study assisted my early research in discovering the effects the FTO gene had on feeding behavior and obesity risk.
Zhao, X., Yang, Y., Sun, B. F., Zhao, Y. L., & Yang, Y. G. (2014). FTO and obesity: mechanisms of association. Current diabetes reports, 14(5), 1-9.
This paper examined how variants of the FTO gene were associated with different disorders including obesity and cancer. It also introduced m6A and FTO’s role in regulating RNA processing. It ultimately summarized the functions and mechanisms of FTO through various studies and highlighted the features linked to obesity. This paper served as the basis for much of my further research regarding m6A and the role that FTO had on RNA epigenetic modifications. It also served as a good summary to tie together the key characteristics of FTO’s functions and mechanisms, which also helped me better understand its role in influencing obesity risk.