Lost in translation

Abstract

Background and objectivesThe insulin-like growth factor (IGF) signaling system is a major arena of intragenomic conflict over embryonic growth between imprinted genes of maternal and paternal origin and the IGF type 1 receptor (IGF1R) promotes proliferation of many human cancers. The 3'-untranslated region (3'-UTR) of the mouse Igf1r mRNA is targeted by miR-675-3p derived from the imprinted H19 long noncoding RNA. We undertook a comparative sequence analysis of vertebrate IGF1R 3'-UTRs to determine the evolutionary history of miR-675 target sequences and to identify conserved features that are likely to be involved in post-transcriptional regulation of IGF1R translation.MethodologySequences of IGF1R 3'-UTRs were obtained from public databases and analyzed using publicly available algorithms.ResultsA very long 3'-UTR is a conserved feature of vertebrate IGF1R mRNAs. We found that some ancient microRNAs, such as let-7 and mir-182, have predicted binding sites that are conserved between cartilaginous fish and mammals. One very conserved region is targeted by multiple, maternally expressed imprinted microRNAs that appear to have evolved more recently than the targeted sequences.Conclusions and implicationsThe conserved structures we identify in the IGF1R 3'-UTR are strong candidates for regulating cell proliferation during development and carcinogenesis. These conserved structures are now targeted by multiple imprinted microRNAs. These observations emphasize the central importance of IGF signaling pathways in the mediation of intragenomic conflicts over embryonic growth and identify possible targets for therapeutic interventions in cancer.

The Evolution of Imprinted microRNAs and Their RNA Targets

“…We have previously analyzed the evolution of the interaction between one imprinted miRNA (miR-675-5p processed from the imprinted H19 RNA) and an unimprinted mRNA ( IGF1R ). We found that the miRNA targeted the most conserved region of the entire 7 kb 3′ UTR of IGF1R [ 21 ]. In the present study, we have found that a deeply-conserved miR-17-5p target site in the PTEN 3′ UTR has been independently targeted by newly-evolved, paternally-expressed, imprinted miRNAs of the C2MC cluster in mice and C19MC cluster in humans.…”

“…We interpret 3′ UTRs as information-processing devices with multiple moving parts that respond to intermolecular interactions with noncoding RNAs and RNA-binding proteins in diverse cellular milieux. For example, Mainieri and Haig [ 21 ] suggested that 3′ UTRs can “read” their cellular milieu and perform simple Boolean computations: If an effect is achieved redundantly by binding of miR-X or miR-Y, this is equivalent to X OR Y; if an effect requires binding of both miR-X and miR-Y, this is equivalent to X AND Y; if miR-Y blocks the effect of miR-X, this is equivalent to X NOT Y; and so forth.…”

“…Cellular responses to a miRNA are dictated by the evolution of targeted sequences, and by the evolution of stimuli that mediate the miRNA’s release, not by the evolution of the miRNA sequence. We have likened a miRNA to a “news report”, or “tweet”, broadcast to the cell about the conditions that led to the miRNA’s release [ 21 ]. In this analogy, a target sequence is an mRNA’s subscription to the news service.…”

Minakata Kumagusu in London: Challenging Eurocentrism in the pages of Nature

“…Frederick Little has discussed how Minakata offered a comparative approach to understanding how ancient Chinese and Indian civilizations developed their constellation systems independently at first, later influencing each other. 49 Minakata suggested that each race does not rely on its 'own plan in the fabrication of constellations.' The Chinese system modelled the stars and constellations on various objects and attributes, such as animals, human actions, and family relations.…”