Collaborative Gene-Silencing Complexes Disable X Chromosomes.

The RIKEN researchers have shed new light on the roles that two protein complexes play in the mysterious process of switching off a single X chromosome in female mammals. This discovery could help researchers work out how certain types of cancer occur in women.

Males have one X chromosome and one Y chromosome, while females have a pair of X chromosomes. This redundancy in the presence of two X chromosomes generally provides mammalian females with additional strength against genetic disorders and cancers compared to males.

During development, females use a mechanism to turn off one of their X chromosomes, known as X inactivation. When this process goes awry, women can develop major health problems such as breast cancer. A deeper understanding of appropriate X chromosome inactivation could help prevent or treat these types of tumor-fueling events in humans.

Now, using mouse embryos, a team led by Haruhiko Koseki of the RIKEN Center for Integrative Medical Sciences (IMS) has shown how two groups of proteins — known as multicellular repressive complex 1 (PRC1) and PRC2 — serve independent and critical roles in helping to maintain a single X chromosome in The developing fetus is in a dormant state. The results have been published in the journal Nature Cell Biology.

Notably, the researchers found that only the supporting tissues of the fetus depend on PRC1 and PRC2 to maintain gene silencing on the inactive X chromosome. In contrast, the same embryonic tissues can maintain the same chromosome in idle mode without the use of these epigenetic regulators, and therefore must rely on some other molecular machinery to accomplish the same function.

“This study indicates differential features of two major tissue lineages in developing embryos,” says Osamu Masui, of IMS.

The researchers determined the functions of PRC1 and PRC2 by studying mice genetically engineered to lack one protein complex or another. These experiments showed how each of the PRC alters DNA coils in different ways each silencing a unique set of genes on the inactive X chromosome.

Both compounds are required for proper inactivation of the X chromosome in additional fetal tissues that will form organs such as the placenta. However, both can be dispensed in the same fetal tissue.

“This study clearly shows that both PRC1 and PRC2 accumulate independently on the inactive X chromosome and differentially maintain X-linked gene silencing,” says Masui. “This discovery could contribute to our understanding of how female-specific tumors form.”

The team is now trying to uncover the molecular mechanisms that allow embryonic tissues to so tightly preserve X chromosome inactivation. “These studies should help us identify the basics of gene regulation in the genome,” says Masui.