One of the mechanisms by which polyadenylation may contribute to the regulation of gene expression (on paper, at least) involves gene pairs that are situated near each other and transcribed convergently. In these instances, polyadenylation and transcription termination need to occur to prevent the production of RNAs that are anti-sense to the two members of the convergently-transcribed gene pair. Overlapping transcripts could lead to the formation of double-stranded RNAs that could in turn trigger regulatory mechanisms, resulting in altered accumulation of the corresponding transcripts.
It is in this vein that a recent study from Gordon Carmichael’s lab at the University of Connecticut is of interest. Briefly, these authors report that the early-to-late transition in gene expression in cells infected with the mouse polyoma virus is accomplished (at least in part) by a reduction in polyadenylation efficiency of the primary transcript encoding the so-called late genes. Interestingly enough, this reduction in polyadenylation efficiency seems to be due to A-to-I editing of the region around the polyadenylation signal. This editing in turn may be traced to an overlap of the early and late transcripts, such that double-stranded RNAs (the substrate for the A-to-I editing complex) that include the late polyadenylation signal are produced and edited before pre-mRNA processing occurs.
Closely-situated convergently-transcribed genes are not uncommon in eukaryotes. This study raises the possibility that RNA editing may be linked to posttranscriptional regulation of such genes. One result presented by Gu et al. showed that knock-down of one of the proteins required for A-to-I editing (ADAR1) does affect the expression of at least one pair of host genes that are convergently-transcribed. Thus, in addition to siRNAs, RNA editing may be important for double-stranded RNA-mediated regulation.
Finally, this study also adds another mechanisms to those known to regulate polyadenylation.
We show here that expression of genes from convergent transcription units can be regulated by the formation of double-stranded RNA (dsRNA) in the region of overlapping polyadenylation signals. The model system employed is the mouse polyomavirus. The early and late genes of polyomavirus are transcribed from opposite strands of the circular viral genome. At early times after infection, the early genes are expressed predominantly. Late gene expression increases dramatically upon the onset of DNA replication, when a major defect in polyadenylation of the late primary transcripts generates multigenomic RNAs that are precursors to the mature late mRNAs. Embedded in these late pre-mRNAs are sequences complementary to the early RNAs that act to down-regulate early gene expression via A-to-I editing of dsRNAs. In this system, the defective polyadenylation, and consequently the production of multigenomic late RNAs, depends on the context, and perhaps also, on the A-to-I editing of the poly(A) signal that overlaps the 3′-end of early transcripts.
Rui Gu, Zuo Zhang, Joshua N. DeCerbo and Gordon G. Carmichael. Gene regulation by sense–antisense overlap of polyadenylation signals. RNA, Published in Advance April 23, 2009, doi: 10.1261/rna.1608909