Alternative polyadenylation and cancer

This is a follow-up of sorts to a previous essay on the subject of alternative polyadenylation.  In the previous report, I discussed some bioinformatics studies that suggested that the 3′ UTRs of mRNAs change, in bulk, in the course of development in mammals.  The implication of these results is that poly(A) site choice in mammals is regulated, with important functional consequences.

A more recent study by Mayr and Bartel adds to this notion.  These authors studied 3′ UTR length in normal and cancer cells, and found a striking correlation between 3′ UTR length and the expression of oncogenes.  Specifically, higher expression (as is found in cancer cells) is correlated with shorter 3′ UTR.  As 3′ UTR length is determined by the position of the poly(A) site along a transcript, this implicates alternative polyadenylation as one mechanism by which oncogene expression is activated.

Norman Ernest Borlaug (March 25, 1914 – September 12, 2009)

Norman Borlaug passed away yesterday.  Dr. Borlaug was the key contributor to the so-called Green Revolution, that brought great food security to countries such as Mexico, Pakistan, and India.  He was a clever and innovative plant breeder and a great champion for the use of high-yielding crop varieties in agriculture.

He was also an outspoken proponent of biotechnology.  As he stated in this short interview:

“I have devoted my life to the global challenge of providing adequate food production for a growing world population.  Forty years ago, a Green Revolution was started using improved seed and fertilizer, helping dramatically increase the harvest while sparing forest and natural areas from the plow.  It took both the scientific advances and the changes in economic policies by leaders to allow for the adoption of the Green Revolution technologies by millions of hungry farmers.

Over the past decade, we have been witnessing the success of plant biotechnology.  This technology is helping farmers throughout the world produce higher yield, while reducing pesticide use and soil erosion.  The benefits and safety of biotechnology has been proven over the past decade in countries with more than half of the world’s population.  What we need is courage by the leaders of those countries where farmers still have no choice but to use older and less effective methods.  The Green Revolution and now plant biotechnology are helping meet the growing demand for food production, while preserving our environment for future generations.”

From his foreword to “The Frankenfood Myth: How Protest and Politics Threaten the Biotech Revolution” by Henry Miller and Greg Conko (Praeger Publishers, 2004):

“As a plant pathologist and breeder, I have seen how the skeptics and critics of the new biotechnology wish to postpone the release of improved crop varieties in the hope that another year’s, or another decade’s, worth of testing will offer more data, more familiarity, more comfort. But more than a half-century in the agricultural sciences has convinced me that we should use the best that is at hand, while recognizing its imperfections and limitations. Far more often than not, this philosophy has worked, in spite of constant pessimism and scare-mongering by critics.

I am reminded of our using the technology at hand to defeat the specter of famine in India and Pakistan in the 1950s and early 1960s. Most “experts” thought that mass starvation was inevitable, and environmentalists like Stanford’s Paul Ehrlich predicted that hundreds of millions would die in Africa and Asia within just a few years “in spite of any crash programs embarked upon.” The funders of our work were cautioned against wasting resources on a problem that was insoluble.

Nevertheless, in 1963, the Rockefeller Foundation and the Mexican government formed the International Maize and Wheat Improvement Center (known by its Spanish acronym CIMMYT) and sent my team to South Asia to teach local farmers how to cultivate high-yield wheat varieties. As a result, Pakistan became self sufficient in wheat production by 1968 and India a few years later.

As we created what became known as the “Green Revolution,” we confronted bureaucratic chaos, resistance from local seed breeders, and centuries of farmers’ customs, habits, and superstitions. We surmounted these difficult obstacles because something new had to be done. Who knows how many would have starved if we had delayed commercializing the new high-yielding cereal varieties and improved crop management practices until we could perform tests to rule out every hypothetical problem, and test for vulnerability to every conceivable type of disease and pest? How much land for nature and wildlife habitat, and topsoil would have been lost if the more traditional, lowyield practices had not been supplanted?

At the time, Forrest Frank Hill, a Ford Foundation vice president, told me, “Enjoy this now, because nothing like it will ever happen to you again. Eventually the naysayers and the bureaucrats will choke you to death, and you won’t be able to get permission for more of these efforts.” Hill was right. His prediction anticipated the gene-splicing era that would arrive decades later. As Henry Miller and Gregory Conko describe in this volume, the naysayers and bureaucrats have now come into their own. If our new varieties had been subjected to the kinds of regulatory strictures and requirements that are being inflicted upon the new biotechnology, they would never have become available.”

Dr. Borlaug had been suggested at times to be the greatest living American.  Given the scope of his accomplishments, it’s hard to argue with this.

“Where Did All the Flowers Come From?”

Carl Zimmer has a good article in the NY Times entitled “Where Did All the Flowers Come From?”   The article summarizes lots of interesting stuff, but I find the speculation regarding the evolution of the endosperm to be particularly though-provoking.  Of course, anytime one mentions genome duplication to me, visions of gene silencing and small RNAs begin dancing in my mind.  A recent article from David Baulcombe’s group merits mention in this context.  This paper describes a developmental study of RNA polymerase IV-derived small interfering RNAs (siRNAs).  The remarkable finding in this paper is the observation that the synthesis of many polIV-derived siRNAs is initated at the onset of the development of the maternal gametophyte, and that these siRNAs are in turn derived from the maternal genome(s) in the endosperm.  This has ramifications for the expression of the different genomes in the endosperm, for genome imprinting, and likely for the evolution of flowers and seed development in plants.

The abstract from the paper:

“Most eukaryotes produce small RNA (sRNA) mediators of gene silencing that bind to Argonaute proteins and guide them, by base pairing, to an RNA target. MicroRNAs (miRNAs) that normally target messenger RNAs for degradation or translational arrest are the best-understood class of sRNAs. However, in Arabidopsis thaliana flowers, miRNAs account for only 5% of the sRNA mass and less than 0.1% of the sequence complexity. The remaining sRNAs form a complex population of more than 100,000 different small interfering RNAs (siRNAs) transcribed from thousands of loci^{1, 2, 3, 4, 5}. The biogenesis of most of the siRNAs in Arabidopsis are dependent on RNA polymerase IV (PolIV), a homologue of DNA-dependent RNA polymerase II^{2, 3, 6}. A subset of these PolIV-dependent (p4)-siRNAs are involved in stress responses, and others are associated with epigenetic modifications to DNA or chromatin; however, the biological role is not known for most of them. Here we show that the predominant phase of p4-siRNA accumulation is initiated in the maternal gametophyte and continues during seed development. Expression of p4-siRNAs in developing endosperm is specifically from maternal chromosomes. Our results provide the first evidence for a link between genomic imprinting and RNA silencing in plants.”

The citation:

Mosher RA, Melynk CW, Kelly KA, Dunn RM, Studholme DJ, Baulcombe DC. 2009.  Uniparental expression of PolIV-dependent siRNAs in developing endosperm of Arabidopsis. Nature 460, 283-286 (9 July 2009) | doi:10.1038/nature08084.

10 and 11

Or, if you might, 24 and 6.

No particular reason – just stumbled across this photo and had to put it here.