Person:

Mainieri, Avantika

Mammalian genomes contain many imprinted microRNAs. When an imprinted miRNA targets an unimprinted mRNA their interaction may have different fitness consequences for the loci encoding the miRNA and mRNA. In one possible outcome, the mRNA sequence evolves to evade regulation by the miRNA by a simple change of target sequence. Such a response is unavailable if the targeted sequence is strongly constrained by other functions. In these cases, the mRNA evolves to accommodate regulation by the imprinted miRNA. These evolutionary dynamics are illustrated using the examples of the imprinted C19MC cluster of miRNAs in primates and C2MC cluster in mice that are paternally expressed in placentas. The 3′ UTR of PTEN, a gene with growth-related and metabolic functions, appears to be an important target of miRNAs from both clusters.

Background: Transcription of the antisense strand of RTL1 produces a sense mRNA that is targeted for degradation by antisense microRNAs transcribed from the sense strand. Translation of the mRNA produces a retrotransposonderived protein that is implicated in placental development. The sense and antisense transcripts are oppositely imprinted: sense mRNAs are expressed from the paternally-derived chromosome, antisense microRNAs from the maternally-derived chromosome.

Results: Two microRNAs at the RTL1 locus, miR-431 and the rodent-specific miR-434, are derived from within tandem repeats. We present an evolutionary model for the establishment of a new self-targeting microRNA derived from within a tandem repeat that inhibits production of RTL1 protein when maternally-derived in heterozygotes but not when paternally-derived.

Conclusions: The interaction of sense and antisense transcripts can be interpreted as a form of communication between maternally-derived and paternally-derived RTL1 alleles that possesses many of the features of a greenbeard effect. This interaction is evolutionary stable, unlike a typical greenbeard effect, because of the necessary complementarity between microRNAs and mRNA transcribed from opposite strands of the same double helix. We conjecture that microRNAs and mRNA cooperate to reduce demands on mothers when an allele is paired with itself in homozygous offspring.

Background and objectives The 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.

Methodology Sequences of IGF1R 3'-UTRs were obtained from public databases and analyzed using publicly available algorithms.

Results A 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 implications The 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.