All cells in an organism have the exact same genetic sequence. What differs between cell types is their epigenetic– meticulously placed chemical tags that affect the genes expressed in each cell. Errors or failures in epigenetic regulation can lead to severe developmental defects in both plants and animals. This raises a puzzling question: If epigenetic changes regulate our genetics, what regulates them?
Scientists at the Salk Institute have now used plant cells to discover that a type of epigenetic tag, called DNA methylation, can be regulated by genetic mechanisms. This new way of targeting plant DNA methylation uses specific DNA sequences to tell the methylation machinery where to anchor. Before this study, scientists had only understood how DNA methylation was regulated by other epigenetic traits, so the discovery genetic Traits can also guide DNA methylation patterns is a major paradigm shift.
These findings could inform future epigenetic engineering strategies aimed at creating methylation patterns predicted to repair or enhance cell function, with many potential applications in medicine and agriculture.
In plants and animals, incorrect DNA methylation patterns can cause developmental defects and in mammals, which can lead to many diseases, including cancer. This makes it very important for us to understand how DNA methylation is targeted to the right sites in the right tissues and developmental stages. Our work answers a long-standing question about how new methylation patterns are created during plant development, which is the first step in thinking about engineering DNA methylation patterns to improve cellular fitness.”
Julie Law, PhD, senior author, biochemist and associate professor at Salk
The study was published in Nature Cell Biology on November 21, 2025 and was funded by both federal research grants from the National Institutes of Health and private philanthropy.
What is epigenetics?
Cellular instructions are written in a language of four letters—A, T, C, and G—that combine to form long chains of DNA. These long, unruly sections of DNA are then wrapped around proteins called histones and packed into a compact with chromatin and strand organization for easy storage and access. The epigenome is a layer of tags and modifications that are made at the top of all these. These changes determine which genes are expressed and which are not without changing the underlying code itself, allowing flexibility in cellular identity and behavior.
A prominent epigenetic tag is DNA methylation, in which a methyl group is attached to specific “C” letters within the DNA code. These DNA methylation tags signal that the underlying DNA needs to be turned off—a process called “silencing.” This process is important not only for regulating gene expression, but also for silencing the expression of specific genetic elements, called transposons. If expressed, transposons can move within the genome, resulting in genome instability and reduced fitness.
Understanding how, when, and why specific DNA methylation patterns are generated in each cell type is crucial for explaining biological development and treating diseases involving epigenetic dysfunction.
“We’ve learned a lot about how an epigenetic tag can be maintained once it’s established,” Law explains. “But cellular diversity does not come from fixed patterns, but from new patterns, and there is much we still don’t know about what creates a new epigenetic pattern. This work fills this gap between knowing the existence of epigenetic diversity and understanding how is produced”.
Why study epigenetics in plants?
Arabidopsis thaliana is a small flowering weed that has served as a staple laboratory plant for decades. Arabidopsis it tolerates experimental perturbations to epigenetic modifications better than human or other animal cells, so it is an excellent resource for investigating fundamental questions about epigenetics.
In ArabidopsisDNA methylation patterns are regulated by a family of four proteins called CLASSYs. Each CLASSY is responsible for recruiting the DNA methylation machinery to different locations within the genome. But before this Salk study, scientists were unclear how CLASSY3 mediated this targeting. What made it choose one set of genomic targets over others?
How do epigenetic changes begin?
Until this point, scientists had only observed DNA methylation events that are targeted by other epigenetic traits. For example, if a section of DNA was already methylated to suppress gene expression in that region, scientists understood how that methylation could be restored to the same site after cell division.
These self-reinforcing mechanisms are particularly important for the maintenance of epigenetic patterns throughout the life of an organism. For example, when an aging skin cell divides into two new skin cells, you wouldn’t want a whole new epigenetic pattern to pop up and suddenly reprogram those skin cells into cancer cells.
But what about the cases where you do Do you want the epigenetic pattern to change such as during development or in response to an environmental stress? How does a plant cell modify its epigenetics to grow, respond and recover?
“How do they make these patterns principle” asks first author Guanghui Xu, PhD, a postdoctoral researcher in Law’s lab. “We wanted to learn what regulates epigenetic pathways to create new DNA methylation patterns during plant development, regeneration, and reproduction.”
A paradigm shift in plant DNA methylation
To investigate how these DNA methylation patterns are derived, the researchers examined Arabidopsis reproductive tissues. Using a forward genetic screen, they discovered a new way to target DNA methylation based on DNA sequences rather than epigenetic features.
Several proteins, which the team named “RIMs,” were found to act with CLASSY3 to establish DNA methylation at specific genomic targets in plant reproductive tissues. These RIMs are a subset of a large class of proteins called REPRODUCTIVE MERISTEM (REM) transcription factors. This was a surprising discovery, as it linked CLASSY3 targeting to specific DNA sequences. When the scientists disrupted these sections of DNA, the entire methylation pathway failed.
The study identifies essential DNA regions where RIMs adapt, after which they can target the DNA methylation machinery to affect neighboring DNA sequences. As a result of this targeting activity, the researchers demonstrated that unique methylation patterns are generated in reproductive tissues expressing different combinations of RIMs. This is the first time scientists have identified a genetic sequence that can drive the epigenetic process of DNA methylation in plants. As there are many REM genes Arabidopsisthe team anticipates that additional family members will be linked to DNA methylation, expanding their roles in controlling epigenetic regulation.
Other Nature Cell Biology The study led by Steven Jacobsen, PhD, at UC Los Angeles used reverse genetics to identify several REM genes involved in regulating DNA methylation through specific DNA sequences—further supporting the role of genetic information in guiding epigenetic processes.
“This finding represents a paradigm shift in the field’s view of how methylation is regulated in plants,” says Law. “All previous work pointed to pre-existing epigenetic modifications as the starting point for targeting methylation, which did not explain how new methylation patterns could arise. We now know that DNA itself can also drive new methylation patterns.”
Armed with these new clues that genetic traits can drive epigenetic changes, researchers have a number of additional questions to explore, including how widespread this new mode of targeting is during plant development and how it can be harnessed to create new DNA methylation patterns. The ability to use DNA sequences to target methylation has broad implications for agriculture and human health, as it would allow correction of epigenetic defects with a high degree of precision.
Other authors include Yuhan Chen, Laura M. Martins, En Li, Fuxi Wang, Tulio Magana, and Junlin Ruan of Salk.
The work was supported by the National Institutes of Health (GM112966, P30 CA01495, P30 AG068635), Salk’s Paul F. Glenn Center for Biology of Aging Research, the Salk Pioneer Postdoctoral Fellowship, the Chapman Foundation, and the Helmsley Charitable Trust.
