Structural conservation versus functional divergence of maternally expressed microRNAs in the Dlk1/Gtl2 imprinting region.
BACKGROUND
MicroRNAs play an important functional role in post-transcriptional gene regulation. One of the largest known microRNA clusters is located within the imprinted Dlk1/Gtl2 region on human chromosome 14 and mouse chromosome 12. This cluster contains more than 40 microRNA genes that are expressed only from the maternal chromosome in mouse.


RESULTS
To shed light on the function of these microRNAs and possible crosstalk between microRNA-based gene regulation and genomic imprinting, we performed extensive in silico analyses of the microRNAs in this imprinted region and their predicted target genes.Bioinformatic analysis reveals that these microRNAs are highly conserved in both human and mouse. Whereas the microRNA precursors at this locus mostly belong to large sequence families, the mature microRNAs sequences are highly divergent. We developed a target gene prediction approach that combines three widely used prediction methods and achieved a sufficiently high prediction accuracy. Target gene sets predicted for individual microRNAs derived from the imprinted region show little overlap and do not differ significantly in their properties from target genes predicted for a group of randomly selected microRNAs. The target genes are enriched with long and GC-rich 3' UTR sequences and are preferentially annotated to development, regulation processes and cell communication. Furthermore, among all analyzed human and mouse genes, the predicted target genes are characterized by consistently higher expression levels in all tissues considered.


CONCLUSIONS
Our results suggest a complex evolutionary history for microRNA genes in this imprinted region, including an amplification of microRNA precursors in a mammalian ancestor, and a rapid subsequent divergence of the mature sequences. This produced a broad spectrum of target genes. Further, our analyses did not uncover a functional relation between imprinted gene regulation of this microRNA-encoding region, expression patterns or functions of predicted target genes. Specifically, our results indicate that these microRNAs do not regulate a particular set of genes. We conclude that these imprinted microRNAs do not regulate a particular set of genes. Rather, they seem to stabilize expression of a variety of genes, thereby being an integral part of the genome-wide microRNA gene regulatory network.
Kircher
Martin
M
Max-Planck-Institut für Informatik, Saarbrücken, Germany. Martin.Kircher@eva.mpg.de
Bock
Christoph
C
Paulsen
Martina
M
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D019295:Computational Biology; D017124:Conserved Sequence; D020862:GC Rich Sequence; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008957:Models, Genetic; D011506:Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA
D020413:3' Untranslated Regions; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C498907:MEG3 non-coding RNA, human; C422882:MEG3 non-coding RNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D011506:Proteins; D062085:RNA, Long Noncoding