NAR’s Breakthrough Articles present high-impact studies answering long-standing questions in the field of nucleic acids research and/or opening up new areas and mechanistic hypotheses for investigation. These articles are chosen by the Editors on the recommendation of Editorial Board Members and Referees. Articles are accompanied by a brief synopsis explaining the findings of the paper and where they fit in the broader context of nucleic acids research. They represent the very best papers published at NAR.
The arginine methyltransferase CARM1 represses p300•ACT•CREMτ activity and is required for spermiogenesis
Arginine methylation, which is carried out by at least 9 enzymes in humans, is implicated in the control and regulation of many biological processes. The fraction of arginine residues that are methylated in the human proteome is reported to rival levels of phosphorylated serine and ubiquitinated lysines, and are known to serve as binding sites for various 'reader' proteins. Carm1, also known as PRMT4, was one of the first arginine methytransferase enzymes shown to function as a transcriptional regulator. It is highly expressed in testes and shown to be translocated to the nucleus during spermatid generation, and was therefore hypothesized to play an important role during spermatogenesis. The studies described in this paper provide direct evidence supporting this biological role, as well as mechanistic details into at least some of the interactions and functions of CARM1 in this capacity.
Extensive and systematic rewiring of histone post-translational modifications in cancer model systems
Studying histone post-translational modifications in cancer offers considerable potential for the discovery of biomarkers for patient stratification and of possible targetable epigenetic mechanisms. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is crucial. The mass spectrometry-based analysis of histone H3 and H4 modifications in a unique collection of primary cultures, cell lines, and mouse xenograft models for three representative tumour types, highlighted many common and time-dependent changes that are determined by culture conditions, and are reverted in cell-derived xenograft models. This study thereby supports the use of short-term cultures, rather than cell lines and long-term primary cultures, for epigenetic studies, and illustrates the need of in vivo validation in xenograft models of cancer.
An interplay of miRNA abundance and target site architecture determines miRNA activity and specificity
In this article, the authors determined experimentally features that govern specialization of members of the let-7 family, which are popular model miRNAs with important functions in development and tumorigenesis. Through in vivo studies in C. elegans, they found that extensive seed-distal pairing promotes specificity, but that the extent of specificity is modest, and insufficient to support robust development, unless target sites also contain an imperfect seed match. Their studies go on to reveal that different target site architectures require different miRNA concentrations for silencing. This challenges a model of ‘one size fits all’, where at a given concentration, a miRNA is either on or off, across all targets. Instead, it supports a rheostat model, where binding site quality and miRNA abundance are integrated into a silencing outcome unique for each target.