Study Elucidates How Cells Make Sense of Transcriptional Direction
At this point, transcription is a relatively well understood process. Researchers understand how genomes copy themselves, at least generally.
But how do cells determine in which direction transcription should proceed?
MIT’s Phillip Sharp, Ph.D., and his colleagues this week show that, in murine embryonic stem cells, “asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation.” Writing in Nature, Dr. Sharp’s team adds that “upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation,” and that PAS signals are the most depleted and U1 small nuclear ribonucleoprotein (snRNP) recognition sites the most enriched sequences in the sense direction relative to the upstream antisense direction.
Dr. Sharp and his colleagues also show that functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction.
The researchers note these findings could help explain how cells initiate and then halt the copying of RNA in the non-coding direction, allowing it to continue downstream such that genes are read correctly.
“This is part of an RNA revolution where we're seeing different RNAs and new RNAs that we hadn't suspected were present in cells, and trying to understand what role they have in the health of the cell or the viability of the cell," Dr. Sharp said in a statement. "It gives us a whole new appreciation of the balance of the fundamental processes that allow cells to function.”
Overall, the researchers suggest that the U1-PAS axis “limits pervasive transcription throughout the genome,” they write.
Dr. Sharp and his colleagues are now investigating how this transcription process related to long, noncoding RNAs, among other things. "Once you see some data like this, it raises many more questions to be investigated, which I'm hoping will lead us to deeper insights into how our cells carry out their normal functions and how they change in malignancy," he said.
“Promoter directionality is controlled by U1 snRNP and polyadenylation signals” was published online in Nature June 23.