Making Sense Out of Antisense RNA Regulation

Inappropriate gene expression can lead to the development of diseases such as cancer. Because of this possibility, cells employ several mechanisms to ensure that their genomes are properly organized and their genes appropriately expressed. These control mechanisms are carried out by proteins and RNAs within the cell, which are themselves subject to regulation.

Strands of RNA that do not code for proteins can play a role in regulating cellular processes. One type of noncoding RNA called antisense RNA is formed when the cell’s gene expression machinery produces an RNA that is complementary to a gene-encoding RNA. When expressed correctly, antisense RNA molecules can manage organization of the chromosomes and regulate gene expression; however, improper accumulation of antisense RNA can have harmful effects on the cell. Cellular mechanisms used to keep potentially detrimental antisense RNA at bay are currently poorly understood.

Martin Zofall, Ph.D., a research fellow working with Shiv Grewal, Ph.D., in the CCR Laboratory of Biochemistry and Molecular Biology, uses yeast models to investigate the manner in which cells regulate gene expression. These studies identified an important role for a protein called H2A.Z in preventing erroneous expression of antisense RNA. A report of the discovery was recently published in Nature.

H2A.Z is a histone, which is a type of protein that interacts with and influences the organization of DNA within the nucleus. Prior to this research, little was known about the activity of H2A.Z other than it was linked to defects in chromosome segregation during cell division. When Zofall and his colleagues engineered yeast cells to lack H2A.Z, they observed a large increase in antisense RNA, suggesting that this histone is involved in suppression of these RNA molecules. Additional experiments showed that H2A.Z achieves this effect through cooperation with other proteins. Simultaneous deletion of the genes that code for these proteins synergistically increases the levels of antisense RNA, pointing to a new mechanism for the control of antisense RNA.

To gain insight into how H2A.Z regulates antisense RNA levels, yeast cells were mutated to eliminate a complex called the exosome, which is responsible for removing unneeded RNA from the cell. The similarities in outcomes when either H2A.Z or the exosome were removed suggest that these two cellular components are part of the same antisense RNA regulatory pathway. The authors conclude that all cells express antisense RNA, but that in yeast cells—and possibly in cells from other species—H2A.Z and other proteins recognize some antisense transcripts and facilitate their degradation by the exosome, thus preventing them from altering gene expression or other cellular processes.

Together, these results suggest that H2A.Z is part of a cellular RNA quality control mechanism that results in degradation of unwanted RNA by the exosome. It is possible that defects in RNA processing caused by loss of H2A.Z could explain in part the errors in chromosome segregation observed when H2A.Z is deleted from cells. This type of genome instability has implications for the initiation of cancer.

Summary Posted: 10/2009


Nature. 2009 Sep 17;461(7262):419-22 PubMed Link