Introduction

Chemical modifications of protein, DNA, and RNA molecules play critical roles in regulating gene expression. Emerging evidence suggests post-transcriptional RNA modifications have major roles in multiple basic biological processes. Epitranscriptomics (also called RNA epigenetics) can be defined as all RNA modifications that exist within a cell. Just as epigenetic modifications regulate gene expression by modulating DNA accessibility, epitranscriptomic changes regulate gene expression by affecting RNA stability, localization, and processing. These chemical modifications are controlled by proteins that function as readers, writers, and erasers (RWEs). Writers and erasers can add or remove specific modifications, respectively, while readers interpret and process them. Studies in yeast, fruit flies, rodents and human models demonstrate that stressors can induce RNA modifications, with specific reprogramming of some regulatory RNAs.

What NIEHS Is Doing

Over 170 RNA base modifications have been identified. (Source: McCown PJ, Ruszkowska A, Kunkler CN, Breger K, Hulewicz JP, Wang MC, Springer NA, Brown JA. 2020. Naturally occurring modified ribonucleosides. Wiley Interdiscip Rev RNA 11(5):e1595. [Abstract])

The NIEHS environmental epitranscriptomics portfolio supports research focused on how environmental exposures affect the epitranscriptome and related health impacts. So far, over 170 RNA base modifications have been identified that have far-reaching impacts on molecular pathways associated with the development and progression of adverse health outcomes. Researchers are using a variety of methods, including cell cultures, animal models and population-based approaches to determine how environmental toxicants impact RNA biology and human health. Changes to the epitranscriptome are also being studied as potential biomarkers of exposure and exposure-induced pathologies.

The portfolio currently has approximately 40 active grants that examine a number of exposures including metals (As, Ni), phosphate, UVB, vinyl chloride, high fat diets (HFDs), and agents that induce reactive oxygen species (ROS). These grants cover a range of health outcomes such as transgenerational metabolic outcomes, lung and cardiovascular disease, cancers, neurodevelopmental and neurodegenerative disorders. There are currently over 100 diseases that are associated with aberrant epitranscriptomic processes. How environmental exposures could impact epitranscriptomics and related disorders is an ongoing area of research.

As our ability to sequence and analyze the epitranscriptome evolves, so too will the research that NIEHS supports. NIEHS-funded environmental epitranscriptomics research could enhance our understanding of how environmental factors influence human health and change how we diagnose and treat disease.

NIEHS Supported Research

Readers, writers, and erasers regulate RNA modifications and their roles in the cell.(Source: Uddin MB, Wang Z, Yang C. 2020. Dysregulations of Functional RNA Modifications in Cancer, Cancer Stemness and Cancer Therapeutics. Theranostics 10(7):3164-3189. [Abstract])

Stress and the Epitranscriptome

The ability of the epitranscriptome to respond to stress is vital for health and survival. One of the most prevalent RNA modifications, m6A, regulates mRNA stability, processing, localization, and translation efficiency depending on its location within the mRNA strand. In response to oxidative stress, the writer proteins METTL3/METTL14 deposit m6A, inducing upregulation of antioxidant genes. DNA damage resulting from UV irradiation also leads to m6A being recruited to the damaged sites and facilitating repair mechanisms. Other reader and writer proteins can also regulate protein translation and lipid metabolism in response to stress.

Exposures and Disease

Environmental exposures can cause changes in the epitranscriptome that contribute to disease pathology, such as liver disease and cancer. METTL3, METTL14, and FTO are writers that deposit m6A on RNA molecules. Overexpression occurs often in cancerous tissues and is associated with worse outcomes in cancer patients. RWEs and m6A dysregulation can be driven by toxic metal exposures such as arsenic, hexavalent chromium, and cadmium. Aberrant m6A modifications play a key role in carcinogenesis and the adverse health outcomes caused by these exposures. METTL3 and FTO have increased expression in fatty liver disease and drive increased m6A profiles in genes important for lipid metabolism. These proteins are impacted by a high fat diet and other exposures, such as vinyl chloride and polychlorinated biphenyls.

Transfer RNA (tRNA) plays a key role in protein translation and is heavily modified. These modifications affect tRNA structure, stability, and function, leading to significant effects on protein translation. Mutations in the enzymes that regulate tRNA modifications can cause multiple types of disorders such as cancer, neurological disorders, and mitochondrial diseases. Of the 75 proteins that have been found to regulate tRNA modifications, 54 have been associated with tRNA modopathies.

Epitranscriptomics and Development

METTL3 is critical during early development as m6A modifications are critical for regulating maternally deposited mRNA in early development. m6A readers and writers are involved in neurodevelopment and important for processes such as neuron differentiation, axon guidance, and astrocyte proliferation. How early exposures might impact the epitranscriptome and drive developmental defects is an ongoing area of study.

Similar to DNA methylation, RNA modifications can also be passed down from parent to offspring. Recent studies have shown that small RNAs in sperm can be passed from one generation to the next. Environmental exposures can modify sperm RNA which contribute to offspring phenotypes in a process referred to as transgenerational inheritance.

Grantees