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Reports Show That Most miRNAs Arise From Few Genes; let-7 May Act as Cancer Marker

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Nearly all mammalian microRNAs originate from fewer than 300 miRNA genes, according to an atlas of mammalian miRNA expression published by an international team of researchers last week in Cell.
 
Additionally, the researchers found “surprisingly … few” miRNAs to be tissue- or cell-type specific.
 
Also last week, researchers from the University of Chicago and Dartmouth Medical School showed that let-7 expression can define two differentiation stages of cancer, making the miRNA a potential marker for advanced forms of the disease.
 
Atlas
 
Writing in Cell, a research team led by investigators at Rockefeller University said that the estimated number of miRNA genes in mammalian genomes has been “steadily increasing, reaching currently tens of thousands.”
 
“Furthermore, the cell type-specific expression of some miRNAs [suggests] that many more miRNAs could surface if only a sufficiently large number of cell types or tissues were studied.
 
“In order to derive [an] miRNA gene-expression atlas that sets into perspective the number and functional relevance of miRNA genes, we have taken the approach of cloning and sequencing … small RNA libraries from different cell types and tissues,” they wrote.
 
Specifically, the team sequenced more than 330,000 independent small RNA sequences from 256 small-RNA libraries. The libraries were prepared from 26 different human, mouse, and rat organ systems and cell types enriched in neuronal, normal, and malignant hematopoietic cells and tissues.
 
When the researchers analyzed various features of the miRNA genes, including sequence conservation and their relationship to genome repeats, they determined that more than 97 percent of all miRNA clones originated from fewer than 300 miRNA genes per species.
 
“We provide evidence for expression of 340, 303, and 205 distinct mature miRNAs from human, mouse, and rat … encoded by 395, 363, and 231 different miRNA genes, respectively,” the researchers wrote in Cell. “When including orthology relationships for cloned miRNAs, we obtained a final list of 416, 386, and 325 miRNA genes present in human, mouse, and rat contained in 214, 190, and 168 transcription units, respectively.”
 
An analysis of the processing patterns for each miRNA revealed that at least 40 percent of the miRNA sequences deposited in the Wellcome Trust Sanger Institute’s miRBase “do not represent the predominantly cloned sequence either because of differences in 3’ or 5’ end processing or because of miRNA/miRNA strand selection.”
 
The team noted that version 8.2 of miRBase includes 84, seven, and 13 additional miRNA gene candidates for human, mouse, and rat, respectively, for which they were unable to find supporting evidence.
 
The researchers also used the miRNA atlas to examine tissue- and cell type-specificity of miRNA expression.
 
“Surprisingly, very few miRNAs were exclusively found in individual tissues or cell types, and only a third of the analyzed miRNAs were expressed with a higher degree of tissue specificity,” they wrote. “When we examined the overall miRNA cloning frequency, we noticed that several abundant miRNAs were ubiquitously expressed, even in embryonic-derived cell lines and tissues.”
 
let-7
 
Also last week, researchers from the University of Chicago and Dartmouth Medical School suggest that miRNA can be a potential marker for advanced forms of the disease because let-7 expression can define two differentiation stages of cancer.
 
“The early phases of carcinogenesis resemble embryonic development, often involving the re-expression of embryonic mesenchymal genes,” the researchers wrote in The Proceedings of the National Academy of Sciences.
 
Previously, the researchers had reported that the NCI60, a panel of 59 human cancer cell lines developed by the National Cancer Institute, can be subdivided into two superclusters of cell types that vary in the way they respond to stimulation of the cell death receptor CD95.
 
The first, SC1, is characterized by a mesenchymal gene signature, while the second, SC2, is characterized by an epithelial gene signature, which suggests that “SC1 cells represent less differentiated, advanced stages of cancer,” they noted.
 

“Surprisingly, very few miRNAs were exclusively found in individual tissues or cell types, and only a third of the analyzed miRNAs were expressed with a higher degree of tissue specificity.”

In the PNAS study, the researchers analyzed an miRNA gene array to determine if miRNAs could be responsible for the differences between SC1 and SC2 cells. They found that the let-7 family of miRNAs is preferentially expressed in SC2 cells
 
Additionally, they found that HMGA2, an early embryonic gene, is a direct let-7 target preferentially expressed in SC1 cells.
Further experimentation using ovarian cancer as a model indicated that let-7 and HMGA2 could serve as prognostic markers for the disease, with low let-7 and high HMGA2 expression indicating advanced cancer.
 
“Our data suggests that human tumors can be divided into two major subtypes,” namely one expressing let-7 at high levels and one expressing the miRNA at low levels, the researchers wrote in PNAS.
 
Further, “the separation of tumor cells into two such [subtypes] may not be restricted to the NCI60 cells,” they noted. “A similar separation into two major clusters was observed in unsupervised, hierarchical cluster analyses of cDNAs in cell lines or primary tumor samples from patients with breast, ovarian, and other cancers.
 
“Recently, the analysis of miRNA expression among different normal tissues also resulted in the separation of tissues into two similar-sized SC,” they wrote in PNAS. “Interestingly, the miRNA that best allowed the separation of these two SCs was let-7a, suggesting that the concept of two SCs separated by their expression levels of let-7 may not be limited to tumor cells.”
 
The researchers wrote that they are now examining whether the loss of let-7 family members can determine cancer progression based on the theory that “one of the functions of let-7 is to maintain differentiated states by suppressing the expression of genes that are expressed in dedifferentiated tissues.”

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