A potential role for intragenic miRNAs on their hosts' interactome

Background: miRNAs are small, non-coding RNA molecules that mainly
act as negative regulators of target gene messages. Due to their
regulatory functions, they have lately been implicated in several
diseases, including malignancies. Roughly half of known miRNA genes
are located within previously annotated protein-coding regions
("intragenic miRNAs"). Although a role of intragenic miRNAs as
negative feedback regulators has been speculated, to the best of
our knowledge there have been no conclusive large-scale studies
investigating the relationship between intragenic miRNAs and host
genes and their pathways. Results: miRNA-containing host genes were
three times longer, contained more introns and had longer 5'
introns compared to a randomly sampled gene cohort. These results
are consistent with the observation that more than 60% of intronic
miRNAs are found within the first five 5' introns. Host gene
3'-untranslated regions (3'-UTRs) were 40% longer and contained
significantly more adenylate/uridylate-rich elements (AREs)
compared to a randomly sampled gene cohort. Coincidentally, recent
literature suggests that several components of the miRNA biogenesis
pathway are required for the rapid decay of mRNAs containing AREs.
A high-confidence set of predicted mRNA targets of intragenic
miRNAs also shared many of these features with the host genes.
Approximately 20% of intragenic miRNAs were predicted to target
their host mRNA transcript. Further, KEGG pathway analysis
demonstrated that 22 of the 74 pathways in which host genes were
associated showed significant overrepresentation of proteins
encoded by the mRNA targets of associated intragenic miRNAs.
Conclusions: Our findings suggest that both host genes and
intragenic miRNA targets may potentially be subject to multiple
layers of regulation. Tight regulatory control of these genes is
likely critical for cellular homeostasis and absence of disease. To
this end, we examined the potential for negative feedback loops
between intragenic miRNAs, host genes, and miRNA target genes. We
describe, how higher-order miRNA feedback on hosts' interactomes
may at least in part explain correlation patterns observed between
expression of host genes and intragenic miRNA targets in healthy
and tumor tissue.