Research Spotlight: Long-Coding RNAs Act as Scaffolds for Assembling Heterochromatin

Mo Motamedi, PhD, an assistant investigator in the Mass General Cancer Center and an assistant professor of Medicine at Harvard Medical School, is the James & Patricia Poitras Endowed Chair in Cancer Research and the senior author of a new paper in Cell, RNA Quality Control Factors Nucleate Clr4/SUV39H and Trigger Constitutive Heterochromatin Assembly

Summary

The human genome contains many repetitive regions which must be maintained in a ‘silent’ state to keep their stability. Loss of silencing of these repeats increases mutations and is linked to several human pathologies, especially cancers.

Despite its importance, how cells establish silencing at repeats is not well understood. In this new study, the research team shows that special RNA molecules, called long noncoding RNAs (lncRNAs), act as scaffolds for the recruitment of all the factors needed to nucleate and assemble heterochromatin—a special structure into which cells package their repetitive DNA regions to silence their expression.

Specifically, they showed that RNA quality control factors target heterochromatin proteins to this lncRNA and together function as epigenetic silencers to repress the expression of repetitive genes in these regions.

This discovery has important ramification for the mechanisms preserving the fidelity of our genome and may yield new therapeutic targets for cancer treatment.

What Questions Were You Investigating in this Study?

We were interested in understanding how cells silence their repetitive DNA regions and package them into heterochromatin. Even though heterochromatin plays a very important role in maintaining genomic stability and preventing mutations, how this process is initiated and established in cells is not fully understood.

Here, we used the fission yeast heterochromatin as a model for understanding this process because many of the protein complexes involved this process are known and their homologs play the same role in human cells.

What Did You Find?

We found that special RNA molecules, called long noncoding RNAs, act as scaffolds for the recruitment of all the factors needed to assemble heterochromatin.

What are the Clinical Implications?

Heterochromatin plays a critical role in preserving the integrity of our genome. In nearly all cancers, heterochromatin is lost, enhancing the tumor’s capacity to mutate, evolve and develop resistance to treatment.

We plan to continue our work in understanding how cells establish heterochromatin molecularly, by developing novel assays to track heterochromatin assembly temporally. We predict that this work will yield novel molecular insight into how cancer cells circumvent this mechanism to survive and resist treatment.

This fundamental knowledge will be required to not only understand this process molecularly, but also develop new therapeutic targets for cancer treatment.

Paper Cited

Khanduja, J. S., Joh, R. I., Perez, M. M., Paulo, J. A., Palmieri, C. M., Zhang, J., Gulka, A. O. D., Haas, W., Gygi, S. P., & Motamedi, M. (2024). RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly. Cell, S0092-8674(24)00468-9. Advance online publication. https://doi.org/10.1016/j.cell.2024.04.042