Diving Deeper into the Epitranscriptomic Landscape and Disease

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In the 1940s the biologist Conrad H. Waddington coined the phrase “epigenetics,” and since then, interest in identifying epigenetic markers on the protein and DNA level has led to the discovery of numerous biomarkers and molecular targets composing the epigenetic landscape. More recently, the modification of RNA molecules within the “epitranscriptome” has gained traction as a driver of human disease through alterations in biological function; however, our understanding of the distinct molecular mechanisms underlying epitranscriptomic events is limited.

N6-methyladenosine (m6A) is the most abundant RNA modification found in mammalian RNAs such as mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). Moreover, m6A is recognized by the YT521-B homology (YTH) domain-containing proteins, which direct complexes to regulate RNA signaling pathways involved in key physiological functions, including RNA metabolism, splicing, folding, and subsequent protein translation.

During the Symposium Session “The Role of Dynamic RNA Modifications in Environmental Response and Disease” at the SOT 58th Annual Meeting and ToxExpo, leaders within the field of epitranscriptomics highlighted novel studies elucidating the molecular mechanisms of RNA modifications and subsequent alterations in cellular signaling pathways for disease. Dr. Chuan He (University of Chicago) discussed the discovery of two novel RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of mRNAs and nuclear RNA such as m6A. Notably, Dr. He showed that exposure to UV or stress stimuli can dysregulate m6A methylation in mammalian cells and that altered YTHD1-dependent protein translation can play a role in memory, behavioral outcomes, and enrichment of neuronal growth within his model system.

The complexity of methyltransferase binding moieties was illustrated by Dr. Yunsun Nam (University of Texas Southwestern Medical Center). Dr. Nam utilized in silico modeling techniques to define how m6A marks are generated by specific RNA methyltransferases (METTL3, METTL14, and METTL16) and how they recognize and catalyze modification of target RNAs. Disease mutations of m6A were shown to alter methyltransferase activity and overall S-adenosylmethionine (SAM) homeostasis, resulting in a widespread impact on the epitranscriptome.

The question whether alterations to the epitranscriptomic landscape affect biological inheritance was discussed in Dr. Qi Chen’s (University of California Riverside) presentation, focused on sperm-mediated intergenerational inheritance. Dr. Chen demonstrated how mental stress, environmental factors, and endocrine disruptors can influence epigenetic modifications of RNA in mammalian sperm, leading to metabolic disorders in offspring. He proposed that sperm RNA (tsRNA and rsRNA) act as epigenetic carriers that encode a sperm RNA code responsible for a specific RNA profile that ultimately influences phenotypic and functional changes in offspring.

Dr. Samie Jaffrey (Weill Cornell Medical College) further discussed how m6A patterns differ in development and disease and illustrated how stress induced by environmental toxicants can alter epitranscriptomic patterns. Dr. Jaffery examined how diverse types of environment stressors (i.e., UV, heat shock, arsenite, and endoplasmic reticulum stress) induce the formation of stress granules that are enriched in mRNAs with modified m6A. Interestingly, his data reveal that a fundamental role of stress granules elicited by diverse toxic insults is to sequester m6A mRNAs and control their translation during and after stress.

Lastly, Dr. Thomas Begley (SUNY Albany) developed a transgenic mouse model that is deficient in the tRNA methyltransferase Alkbh8, which is required for the formation of 5-methoxycarbonylmethylluridine (mcm5U) and mcm5Um on tRNA for redox-sensitive proteins. Alkbh8-/- cells demonstrated decreased levels of selenoproteins that are important for detoxification of reactive oxygen species generation. Further, to compensate for the epitranscriptomic deficiency, Alkbh8-/- cells and lung tissue were shown to be reprogrammed transcriptionally to upregulate complementary stress response and damage mitigation systems. 

Overall, this session highlighted roles of RNA modification on biological function and human disease. It is important to note that the field of epitranscriptomics is in its infancy, and gaining a better understanding of the roles of RNA modifications and the distinct underlying mechanisms that influence disease outcomes is imperative in order to identify epitranscriptomic biomarkers and molecular targets for the development of novel risk mitigation strategies and therapeutic interventions, especially in relation to induced toxicant exposures.

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.

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