Revising the Genetic Message after It Is Sent

DNA is sometimes likened to instructions in a manual but, unlike the usual manual, it contains information that can change over time. Chemical tags can attach themselves to the DNA at millions of positions, modifying the genetic instructions. These tags have been extensively studied, but the possibility for change does not end there. The DNA message, it turns out, can be modified even after it has been “sent”: Chemical tags also attach themselves to molecular messengers –  messenger RNAs, or mRNAs for short – the transient molecules that convey the formula for making proteins from DNA to the cell’s protein-making machinery. In a study reported in Nature, researchers at the Weizmann Institute of Science have revealed the workings of a particular modification to the mRNA and shown that it can dramatically alter the genetic message.  

More than a hundred of these mRNA modifications are thought to exist, but a mere handful are thus far known to science. Their significance has been recognized only in the past few years. Scientists have realized that these modifications represent, in effect, a previously unrecognized mechanism of gene regulation – they can boost or reduce gene activity or even cause a gene to be turned on or off. As a result, they play a role in most biological processes and are involved in a variety of diseases.

More than a hundred of these mRNA modifications are thought to exist, but a mere a handful are thus far known to science

In a new study, Dr. Schraga Schwartz of Weizmann’s Molecular Genetics Department, together with colleagues, developed a new approach to studying mRNA modifications. They applied this approach to a modification called m1A, which involves the attachment of a chemical tag known as a methyl group to one particular mRNA building block, the A nucleotide. Schwartz and his team generated maps of this modification across the entire genome, identifying all the m1A sites with unprecedented precision. In addition, they identified the enzymes that cause mRNAs to undergo an m1A modification.

The scientists discovered that m1A occurs much less frequently than previously thought, but that it can radically change the way the mRNA message is “perceived.” The tag can, essentially, cause the cell to “ignore” the mRNA message, with far-reaching consequences. In one case, for example, in a newly formed embryo – when it is made up of only eight cells – m1A marks a crucial gene in the mitochondria, the cell’s energy “factories,” thereby serving as a potential switch that alters the way the embryo’s cells produce the molecular fuel needed to sustain their existence. Apparently, m1A can cause the cells to switch from breaking down glucose as a source of energy to deriving energy from the mitochondria.

The advantage of mRNA modification

These findings shed new light on the very basis of cellular life and may prove useful for the study of disorders in which energy production is altered. The latter include various malignancies: Cancer cells, unlike most healthy cells, largely rely on the breakdown of glucose for making their fuel, which, among other things, enables them to survive within the oxygen-starved environment of the tumor.

Why do cells use mRNA modification to regulate genes when they have all sorts of other mechanisms for managing gene expression – for example, the production or degradation of entire mRNA molecules? “Different kinds of gene regulation must have evolved because each of them offers advantages in different situations,” Schwartz says. “It’s possible that mRNA modifications are most suitable for the rapid modulation of gene activity – that is, for rapidly turning gene expression up or down in response to a stimulus.”

The methods applied by Schwartz and his colleagues to the study of m1A may advance the study of other mRNA modifications and help investigate the diseases that arise when the enzymes producing these modifications are mutated. These include obesity, cancer and neurodegenerative diseases.

The research team included senior intern Dr. Modi Safra; postdoctoral fellows Drs. Aldema Sas-Chen, Ronit Nir and Dan Bar-Yaacov, PhD student Roni Winkler; and staff scientist Aharon Nachshon. The research was conducted in collaboration with departmental colleague Dr. Noam Stern-Ginossar, and with Dr. Matthias Erlacher of the Medical University of Innsbruck and Dr. Walter Rossmanith of the Medical University of Vienna.

Devoted to research

Schraga Schwartz was just one year away from becoming a medical doctor when he decided to devote himself to research instead. By then he had already completed a BSc in medicine cum laude at Tel Aviv University and was pursuing an MD-PhD program; but he dropped out of medical studies before earning his MD degree. “Both professions are gratifying and both have the potential of benefitting humanity. But I enjoyed research so much more,” he says. After a year as a postdoctoral researcher in the lab of Prof. Rotem Sorek in Weizmann’s Molecular Genetics Department, he served as a postdoctoral fellow at the Broad Institute of Harvard and at MIT until joining the Weizmann faculty in 2015. He was elected an EMBO Young Investigator in 2017.

Dr. Schraga Schwartz's research is supported by the David and Fela Shapell Family Foundation INCPM Fund for Preclinical Studies; the Abramson Family Center for Young Scientists; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Berlin Family Foundation New Scientist Fund; the estate of David Turner; and the European Research Council. Dr. Schwartz is the incumbent of the Robert Edward and Roselyn Rich Manson Career Development Chair in Perpetuity.