Environmental Factor – July 2022: Planning a Giant Leap: Workshop Charts the Path to RNA Sequencing


The enormous effort to sequence the human genome – which resulted in a complete map of every fragment of human DNA – has led to incredible advances in our understanding of human biology and in the treatment of disease. Yet the sequencing of RNA, which is DNA’s chemical cousin, remains elusive.

While sequencing the human genome can now be done in hours thanks to advances in technology, the promise of doing the same for RNA lies on the other side of a collaborative effort.

To that end, RNA sequencing research and collaborations between scientists and clinicians were the focus of a workshop held May 24-26. The event was organized by the NIEHS and the National Institute for Human Genome Research (NHGRI). Over six sessions, researchers discussed a range of topics, from technologies that will help sequence RNA to ways to advance innovation in RNA-based therapies.

“This gathering is an excellent opportunity to explore the current state of knowledge, opportunities and needs for a product of the genome, RNA,” said Eric Green, MD, Ph.D., director of the NHGRI. Both institutes, he said, seek to “fully and completely understand the role of RNA in human biology, health and disease.”

Green, left, and NIEHS Director Rick Woychik, Ph.D., provided opening remarks and outlined the workshop objectives. (Photos courtesy of NHGRI and NIEHS, respectively)

Workshop participants discussed the current capabilities of “RNomics” – as the field is colloquially known – as well as the prospects for fully characterizing the true diversity of RNA and its known chemical and structural modifications.

Getting to Know RNA

The sequence of RNA determines its structure, and this can influence its biological activity. The shape of an RNA molecule can influence the other molecules it interacts with, affecting its function. There is growing interest in understanding how environmental exposures involving polychlorinated biphenyls (PCBs), heavy metals, and other substances can influence the molecular mechanisms responsible for RNA modifications.

Viviane Cheung In a recent NIEHS Director’s Corner conversation, Cheung spoke with Woychik about the importance of RNA sequencing. (Photo courtesy of Vivian Cheung)

Participants noted that this area of ​​study, called environmental epitranscriptomics, could help researchers link changes in RNA to health outcomes such as metabolic disorders, lung disease and cancer. Since 2018, the NIEHS has supported dozens of grants in the field.

Pioneer in RNA biology and workshop moderator Vivian Cheung, MDfrom the University of Michigan, said even sequencing a few versions of RNA, or “transcripts,” could help researchers understand which chemical changes are biologically important.

“I would be very happy if we knew 10 transcripts to give us an idea of ​​where the modifications are, what sequences are nearby, how they affect the structure and how they change throughout the lifetime of this RNA,” Cheung said.

RNA in 3D

When used as a drug itself or as a drug target, RNA can influence health outcomes, a field known as RNA therapy. The field has recently seen success, notably when researchers used a type of RNA called messenger RNA (see box) to develop COVID-19 vaccines.

Although the knowledge base of RNA-based therapies has advanced significantly over the past few decades, the pharmaceutical industry has largely focused on the same old targets: proteins.

“Despite the fact that more than 98% of the genome is non-coding [meaning it does not code for proteins]the vast majority of drugs in development today in the pharmaceutical industry target one of 700 disease-related proteins,” said Jeannie Lee, MD, Ph.D. from Harvard Medical School.

Jeannie Lee In 2020, Lee delivered the NIEHS Hans L. Falk Memorial Lecture, describing his research on X-chromosome inactivation, which affects female embryonic development. (Photo courtesy of Jeannie Lee)

If researchers could target RNA molecules, they could dramatically expand the chemical space in which drugs could be engineered, she said. Although barriers exist, small molecule drugs made available to patients orally could penetrate cells and help target RNA. A growing number of startups are investigating this method.

In his research, Lee discovered that RNA can be systematically targeted by small molecules. His lab also discovered that these candidate small molecules can be screened without advanced knowledge of the 3D structure of RNA. She recently published a study suggesting that such drug-like compounds can disrupt the structure of a specific RNA and potentially alter its function. Future work could focus on developing a library of small molecules designed specifically for RNA.

Innovation is key

RNA sequencing will require innovative research approaches and a significant amount of data collection and analysis. To achieve this, scientists must advance more robust computational tools, noted NIEHS Director Rick Woychik, Ph.D.

“We need to do a better job of spreading knowledge about RNomics technologies and distributing state-of-the-art RNomics instruments,” he said. “That’s why workshops like this are so important – they spark the ideas and collaborations that pave the way for innovation.”

(Susan Cozier is a contract writer for the NIEHS Office of Communications and Public Liaison.)


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