About this Research Topic
In vivo gain- and loss-of-function studies in mouse models demonstrate without a doubt that microRNAs (miRNAs), alongside with coding genes, control mammalian biological systems. The regulation of miRNA expression is tightly controlled, and often the same rules and regulations that govern coding gene expression also apply to miRNAs. Similar to coding genes, altering the levels and the temporal expression of a specific miRNAs clearly affects the proper development and function of the tissue where it is expressed. Therefore, it is reasonable to argue that the dysregulated control of miRNA expression would give rise to diseases as has been well established for coding genes. Along the same line of reasoning, there is an impetus to use miRNAs as diagnostic biomarkers and to develop therapeutic agents to target miRNAs for the treatment of various diseases.
However, there is a dearth of genetic studies in humans to identify mutations that cause altered miRNA expression in diseases, and mouse models that recapitulate these conditions by introducing such mutations. One of only a few good examples is how the targeted deletion of the LEU2/miR-15a/16-1 region in mice faithfully recapitulates disease states found in a subset of CLL patients. What accounts for the paucity of human genetic evidence to implicate miRNAs in human diseases? Is it because most miRNAs do not act as master regulators of gene expression, but rather as modifiers of gene levels? Or do most miRNAs reside in more stable genomic regions that are protected from agents that induce genetic instability. Or perhaps the direction of research carried out by miRNA biologists precludes the identification of genetic evidence implicating miRNAs in human diseases? The answer is probably all of the above. While the first two issues are beyond our ability to address since we cannot change the nature of biology, we could redirect our effort in searching for a link between miRNAs and human diseases by focusing on genetic or epigenetic changes to miRNA genes that drive miRNA expression changes during disease manifestations that are functionally significant in mouse models. At this stage, the miRNA biology field does not need any more in vitro studies documenting the expression pattern of miRNAs in human diseases, but does require in depth genomic and in vivo functional studies, such as the one described for the DLEU2/miR15a/16-1 in CLL, to definitively draw meaningful connections between altered miRNA expression/function and human diseases. Finally, we also need to direct our resources and efforts towards understanding the relationship between miRNAs and their targets, including novel ways to study how miRNAs repress multiple targets within a given cell type to regulate specific cellular functions.
The aim of this Special Research Topics is to engage researchers in discussions and brain storming sessions to advance the miRNA field beyond expression profiling studies, and towards a greater understanding of how miRNAs become dysregulated and impact human diseases through their modulation of critical target genes.
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