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Genomics in the Journals: Feb 21, 2013

NEW YORK (GenomeWeb News) – Mutations affecting a pair of related enzyme-coding genes can contribute to the risk of benign glandular tumors called adenomas and secondary hypertension, a new Nature Genetics study suggests. An international team led by investigators in Germany performed exome sequencing on matched tumor and normal samples from nine individuals with forms of adenoma that enhance aldosterone hormone production. This leads to a type of so-called aldosteronism that can bump up blood pressure and cause other adverse symptoms.

When researchers sorted through the exome sequence data, they saw ties between aldosterone-producing adenoma and mutations in two ATPase genes — ATP1A1 and ATP2B3 — that participate in sodium/potassium and calcium signaling, respectively. Somatic ATP1A1 mutations turned up in more than 5 percent of 308 aldosterone-producing adenoma samples screened subsequently, the team noted, while 1.6 percent of those tumors contained ATP2B3 alterations.

"[T]hese findings expand the spectrum of somatic alterations leading to [aldosterone-producing adenomas] to two members of the P-type ATPase pump family, extend knowledge of the molecular mechanism leading to [aldosterone-producing adenoma]," the Ludwig Maximilian University of Munich researcher Martin Reincke, the study's corresponding author, and colleagues wrote, "and indicate new potential therapeutic targets for the most frequent secondary form of arterial hypertension."

A BMC Plant Biology study by Australian researchers hinted that a combination of gene expression shifts and genetic variation in some plants can stave off the predation of certain leaves. The group did Roche 454 sequencing on messenger RNA transcripts isolated from collections of leaves from the same Eucalyptus melliodora tree. The two leaf chemotypes had distinct secondary metabolite contents, which corresponded to a higher or lower risk of being nibbled by predators.

Through gene set enrichment and other analyses, the researchers uncovered examples of differential expression between the leaf chemotypes, including expression shifts involving genes that contribute to the production of protective secondary metabolites called terpenes. Investigators also identified 10 genetic variants that seemingly coincided with the Eucalyptus chemotypes, with at least some of those SNPs falling in and around terpene-related genes.

Together, such subtle genetic alterations seem to influence the monoterpene and sesquiterpene representatives present in leaves, study authors said, as well as leaf levels of other secondary metabolites such as the formylated phloroglucinol compounds, or FPCs.

"Leaves which were resistant to predation had five fewer monoterpenes and nine fewer sesquiterpenes than the tastier leaves," senior author Amanda Padovan, a biologist with the Australian National University, said in a statement.

"However," she added, "the concentration of FPCs and the remaining monoterpenes was far higher. So it seems that these mutations reduce the tight control over terpene production."

In Nature, researchers based in Germany, the Netherlands, and France described a microRNA that appears to have a role in heart tissue aging and related changes to the organ's function. The team first tracked down this miRNA, called miR-34a, with array-based miRNA profiling experiments that compared heart samples from young mice (between one- and two-months old) with samples from more mature mice (those that had lived some 18 to 20 months).

There, miR-34a showed enhanced expression in the older mouse hearts — a pattern that the study's authors went on to verify in 21 human heart biopsy samples. Their follow-up experiments suggested that miRa-34a's influence on cardiac aging and function stems from its inhibition of PNUTS, a protein that apparently blocks apoptosis and other age- or damage-related effects in heart muscle cells called cardiomyocytes.

"Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during aging and after acute myocardial infarction, by inducing DNA damage response and telomere attrition," senior author Stefanie Dimmeler, a researcher affiliated with Goethe University Frankfurt's Institute for Cardiovascular Regeneration and the German Center for Cardiovascular Research, and colleagues noted.

A Yale University-led group reporting in Developmental Cell provided evidence suggesting epigenetic patterns in fruit fly cells are mediated, in part, by the Piwi protein and small RNAs — or piRNAs — that interact with it. Building on results from a 2007 study that uncovered more limited examples of epigenetics-related Piwi-piRNA complex binding in the Drosophila genome, researchers used Piwi-targeted chromatin immunoprecipitation coupled with sequencing or quantitative PCR to map and verify Piwi-piRNA binding sites in fruit fly cells.

In the process, they uncovered sequences complementary to piRNAs across the fruit fly genome, particularly around transposons and repetitive sequences. Details of the piRNA and Piwi protein interactions with such sequences seem to depend somewhat on whether heterochromatic or euchromatic sequences are considered, the study's authors noted.

In general, though, their follow-up experiments suggested that, after interacting with piRNA complementary sequences, the small RNAs draw in Piwi, which is followed by other epigenetic factors, leading to changes in nearby histone methylation patterns, RNA polymerase II binding, and so on.

"This is the first major mechanism discovered that controls where epigenetic factors — the gene switches — are to be placed in the genome," senior author Haifan Lin, Yale Stem Cell Center director, said in a statement.

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.