Abstract
BackgroundThe continuing discovery of new types and functions of small non-coding RNAs is suggesting the presence of regulatory mechanisms far more complex than the ones currently used to study and design Gene Regulatory Networks. Just focusing on the roles of micro RNAs (miRNAs), they have been found to be part of several intra-pathway regulatory motifs. However, inter-pathway regulatory mechanisms have been often neglected and require further investigation.ResultsIn this paper we present the result of a systems biology study aimed at analyzing a high-level inter-pathway regulatory motif called Pathway Protection Loop, not previously described, in which miRNAs seem to play a crucial role in the successful behavior and activation of a pathway. Through the automatic analysis of a large set of public available databases, we found statistical evidence that this inter-pathway regulatory motif is very common in several classes of KEGG Homo Sapiens pathways and concurs in creating a complex regulatory network involving several pathways connected by this specific motif. The role of this motif seems also confirmed by a deeper review of other research activities on selected representative pathways.ConclusionsAlthough previous studies suggested transcriptional regulation mechanism at the pathway level such as the Pathway Protection Loop, a high-level analysis like the one proposed in this paper is still missing. The understanding of higher-level regulatory motifs could, as instance, lead to new approaches in the identification of therapeutic targets because it could unveil new and “indirect” paths to activate or silence a target pathway. However, a lot of work still needs to be done to better uncover this high-level inter-pathway regulation including enlarging the analysis to other small non-coding RNA molecules.
Highlights
The continuing discovery of new types and functions of small non-coding RNAs is suggesting the presence of regulatory mechanisms far more complex than the ones currently used to study and design Gene Regulatory Networks
We identified three additional low-score miR-1976 targets in the mTOR pathway, which are Pathway Antagonist Genes (PAGs) Transcription Factors involved in Pathway Protection Loop (PPL)
The discovery of the Pathway Protection Loops is suggesting a level of transcriptional regulation at the pathway level not fully investigated before
Summary
The continuing discovery of new types and functions of small non-coding RNAs is suggesting the presence of regulatory mechanisms far more complex than the ones currently used to study and design Gene Regulatory Networks. Just focusing on the roles of micro RNAs (miRNAs), they have been found to be part of several intra-pathway regulatory motifs. Systems biology is increasingly highlighting that a discrete biological function can only rarely be attributed to a single molecule. In order to move toward the identification of higher-level mechanisms of transcriptional regulation, in this paper we performed a systemic analysis on a large set of well known biological networks to underline the presence of an inter-network regulatory motif in which miRNAs seem involved in a high-level regulatory activity among different networks. Rather searching for pure topological motifs, available networks have been enriched with biological information from several public repositories to attempt to link obtained results to selected biological mechanisms [23]
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