An interesting discovery -- and topical for a few of the on-going discussions 
on this list -- of how much more is going on than we had previously thought was 
going on, during the transcription process from a cell's DNA that ultimately 
leads to the production of viable mRNA and the expression of the encoded amino 
acid chain. Here is yet another mechanism whereby the ultimate expressed 
genetic information of a life form is influenced by a environmental feedback 
mechanism which causes genes that are not normally expressed to become 
It seems to me that life has evolved multiple pathways of control and multiple 
encoding schemas that are operating on top of the foundational DNA encoding 
that most life (except the few RNA life forms) relies on as the ultimate 
repository of genetic information.
A new gene-expression mechanism is a minor thing of major importance
A rare, small RNA turns a gene-splicing machine into a switch that controls the 
expression of hundreds of human genes. Howard Hughes Medical Institute 
Investigator and professor of Biochemistry Gideon Dreyfuss, PhD, and his team 
from the Perelman School of Medicine at the University of Pennsylvania, 
discovered an entirely new aspect of the gene-splicing process that produces 
messenger RNA (mRNA). 
The investigators found that a scarce, small RNA, called U6atac, controls the 
expression of hundreds of genes that have critical functions in cell growth, 
cell-cycle control, and global control of physiology. Their results were 
published in the journal eLife.
These genes encode proteins that play essential roles in cell physiology such 
as several transcription regulators, ion channels, signaling proteins, and DNA 
damage-repair proteins. Their levels in cells are regulated by the activity of 
the splicing machinery, which acts as a valve to control essential regulators 
of cell growth and response to external stimuli.
Dreyfuss, who studies RNA-binding proteins and their role in such diseases as 
spinal muscular atrophy and other motor neuron degenerative diseases, describes 
the findings as "completely unanticipated."
Complicated Splicing
As DNA is transcribed into RNA and then into the various proteins that perform 
the functions of life, non-coding gene sequences (introns) need to be removed 
from the transcribed RNA strand and the remaining gene sequences (exons) joined 
together. This is the job of specialized molecular machinery called the 
spliceosome. There are two varieties of spliceosomes, the so-called major and 
minor. The major spliceosome is by far the most abundant, such that the role of 
its minor counterpart is often disregarded.
"Most of the time the minor spliceosome, which has similar but not identical 
components to that of the major, isn't even mentioned," says Dreyfuss. With 
each type of spliceosome recognizing different splicing cues, the major 
spliceosome acts on the vast majority of introns (>200,000) and the minor one 
splices the several hundred minor-type introns. 
But the evolutionary persistence and role of the minor spliceosome has been a 
puzzle to scientists, since the minor introns it targets are far outnumbered by 
the major introns handled by the major spliceosome, and the minor spliceosome 
is often inefficient. But the mRNAs produced from genes that have a minor 
intron are not ready until all their introns, both major and minor, are 
spliced. Thus a single inefficiently spliced minor intron can hold up 
expression – mRNA and protein production – for an entire gene. Researchers have 
therefore wondered why the apparently superfluous minor spliceosome hasn't been 
eliminated altogether through normal evolution.
"One looks at it and asks, we've known that minor spliceosomes are inefficient, 
why even bother to keep them under evolution's relentless selection pressure?" 
notes Dreyfuss. "It's been difficult to rationalize the conservation of minor 
introns and the minor spliceosome on the basis of splicing alone, as with few 
cue changes this function could simply have been performed by the major 
More to the Minor
Dreyfuss's team discovered that there's more to the minor spliceosome while 
investigating the effects of different physiological conditions such as cell 
stress, transcription, and protein synthesis on small noncoding RNAs. "We 
inhibited transcription and then measured what happens to the amount of each of 
the small noncoding RNAs three or four hours later," he explains. "That's when 
we noticed that U6atac levels plunged." They found that U6atac, which is also 
the catalytic component of the minor spliceosome, is extremely unstable in a 
cell. "If you stop the transcription of U6atac, you stop producing it, and very 
quickly its levels become terribly low. And we knew that it's already one of 
the rarest snRNAs in cells. So we thought this surely will have an effect on 
minor intron splicing."
To test for such effects, the researchers deliberately knocked down U6atac in 
cells and then did genome-wide RNA sequencing. "We noticed that when you knock 
down U6atac, each minor intron responds differently," notes Dreyfuss. "Some of 
them showed that they're very inefficient and highly sensitive to U6atac level, 
which is an explanation for why the mRNA from those genes doesn't express 
well." Low U6atac levels within cells limit the rate of minor intron splicing, 
and thus the expression of important genes containing those minor introns.
Next, says Dreyfuss, "we started looking for any conditions where the levels of 
U6atac might be increased, so that the less efficient genes will be able to 
express. Out of the various conditions that we surveyed, we found that cell 
stress, which activates the p38MAPK pathway, causes a very large and rapid 
increase in U6atac and with that, a huge enhancement of the splicing of those 
minor introns that otherwise splice very inefficiently." (p38MAPK is a key 
component of cell signaling pathways that are activated during cell stress such 
as the release of inflammatory cytokines, ultraviolet radiation, heat, and 
osmotic shocks, so p38MAPK play an important role in cellular growth and 
differentiation, apoptosis, cancer, and autophagy).
A Valve and a Splicer
Sure enough, when U6atac levels are rapidly and steeply increased, "the 
bottleneck to the production of mRNA from those few hundred genes that contain 
a minor intron is removed." The p38MAPK signaling pathway – when activated 
under cell stress—is one of potentially many ways in which U6atac levels can be 
When minor spliceosome activity is reduced, the minor introns are retained in 
the mRNA while the major introns are spliced out. This signals the mRNA for 
degradation, limiting the expression of genes that contain minor introns.
The findings point to an entirely new and vital role for the minor spliceosome 
and particularly its U6atac component. More than simply splicing out minor 
introns, U6atac actually functions as a control and regulatory mechanism for 
minor intron-containing genes. "We propose that the minor spliceosome was 
conserved because it's used as a valve, not simply a spliceosome," Dreyfuss 
says. "It's a very important switch and it's an unexpected kind of mechanism."
Dreyfuss sees parallels between the discovery of U6atac's role in splicing and 
previous work by his lab that revealed the importance of U1, a major 
spliceosome component, in preventing the premature termination of mRNA 
transcription. "That was completely unanticipated and is a major area of 
interest, because this is a major way of regulating the transcriptome and mRNA 
One of the team's next steps will be to determine exactly how p38MAPK, and 
possibly other molecules, acts to control U6atac levels.
Meanwhile, they have demonstrated the "folly" of casually disregarding the 
seemingly unimportant. "This provides a new perspective on minor introns and 
minor spliceosomes, because it's been a real mystery," says Dreyfuss.

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