Amazing stuff!
"... After the RNAs are produced in the nucleus, some stay there to regulate gene expression, but most – especially those that carry the recipes for proteins – are slated to leave the nucleus for the cytoplasm, where proteins are manufactured. Previous studies aiming to clarify how RNAs get to their assigned locations had produced conflicting results. ...
tested the zip code hypothesis using a technique known as a “massively parallel RNA assay,” ... The technique makes it possible to study thousands of different RNAs simultaneously, obtaining results within days instead of the years it would previously have taken to study these same RNAs one by one. The scientists inserted thousands of different RNA segments into various “host” RNA molecules – linear or circular – copies of which were then introduced into millions of cells. After separating the nucleus from the cytoplasm of these cells, the researchers could tell where their RNAs had ended up. ...
After investigating some 8,000 genetic segments in this manner ... found that several dozen of them indeed serve as zip codes. These zip codes instruct some RNAs to stay in the nucleus, tell others to move into the cytoplasm immediately, and direct still others to make this move only after lingering in the nucleus for a while. The researchers also discovered several proteins that serve as “postal clerks” whose job it is to bind to RNAs, “read” their zip codes and dispatch the RNAs to the locations encoded there. ...
Remarkably, there was a clear-cut division between linear and circular RNAs within this “postal system.” To begin with, the same zip code could assign an RNA to a different location, depending on whether it was linear or circular. Moreover, two sets of postal clerks ran the sorting, one for the linear RNAs and one for the circular. In fact, each of the clerks issued their own specific kind of instructions. For example, one protein, called IGF2BP1, bound mainly to linear RNAs, promoting their export from the nucleus. Another one, called SRSF1, specialized in directing circular RNAs to stay in the nucleus. ..."
tested the zip code hypothesis using a technique known as a “massively parallel RNA assay,” ... The technique makes it possible to study thousands of different RNAs simultaneously, obtaining results within days instead of the years it would previously have taken to study these same RNAs one by one. The scientists inserted thousands of different RNA segments into various “host” RNA molecules – linear or circular – copies of which were then introduced into millions of cells. After separating the nucleus from the cytoplasm of these cells, the researchers could tell where their RNAs had ended up. ...
After investigating some 8,000 genetic segments in this manner ... found that several dozen of them indeed serve as zip codes. These zip codes instruct some RNAs to stay in the nucleus, tell others to move into the cytoplasm immediately, and direct still others to make this move only after lingering in the nucleus for a while. The researchers also discovered several proteins that serve as “postal clerks” whose job it is to bind to RNAs, “read” their zip codes and dispatch the RNAs to the locations encoded there. ...
Remarkably, there was a clear-cut division between linear and circular RNAs within this “postal system.” To begin with, the same zip code could assign an RNA to a different location, depending on whether it was linear or circular. Moreover, two sets of postal clerks ran the sorting, one for the linear RNAs and one for the circular. In fact, each of the clerks issued their own specific kind of instructions. For example, one protein, called IGF2BP1, bound mainly to linear RNAs, promoting their export from the nucleus. Another one, called SRSF1, specialized in directing circular RNAs to stay in the nucleus. ..."
From the abstract:
"Long RNAs vary extensively in their post-transcriptional fates, and this variation is attributed in part to short sequence elements. We used massively parallel RNA assays to study how sequences derived from noncoding RNAs influence the subcellular localization and stability of circular and linear RNAs, including spliced and unspliced forms. We find that the effects of sequence elements strongly depend on the host RNA context, with limited overlap between sequences that drive nuclear enrichment of linear and circular RNAs. Binding of specific RNA binding proteins underpins some of these differences—SRSF1 binding leads to nuclear enrichment of circular RNAs; SAFB binding is associated with nuclear enrichment of predominantly unspliced linear RNAs; and IGF2BP1 promotes export of linear spliced RNA molecules. The post-transcriptional fate of long RNAs is thus dictated by combinatorial contributions of specific sequence elements, of splicing, and of the presence of the terminal features unique to linear RNAs."
Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs (open access)
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