FD is a rare inherited disease caused by a single point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA and reduction of the IKAP protein. Previously, investigators had demonstrated that defective SMN2 splicing could be corrected using an antisense oligonucleotide (ASO), leading to an approved therapy for spinal muscular atrophy. In this manuscript, investigators identified antisense oligonucleotides (‘ASOs’) that correct the splicing of human IKBKAP pre-mRNA and reveal cisregulatory elements that controls its splicing. By systematically screening ASOs with uniformly modified 2’-Omethoxyethylribose (MOE)-phosphate backbone, they identified candidates that enhance retention of exon 20 during pre-mRNA splicing. This work provides deeper insights into the mechanisms of IKBKAP exon 20 splicing and sets the stage for the clinical development of antisense FD therapeutics.
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.
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.
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.
