Editing Small interfering RNA (section)

=== Saturation of the RNAi machinery ===
siRNAs transfection into cells typically lowers the expression of many genes, however, the upregulation of genes is also observed. The upregulation of gene expression can partially be explained by the predicted gene targets of endogenous miRNAs. Computational analyses of more than 150 siRNA transfection experiments support a model where exogenous siRNAs can saturate the endogenous RNAi machinery, resulting in the de-repression of endogenous miRNA-regulated genes.<ref>{{cite journal | vauthors = Khan AA, Betel D, Miller ML, Sander C, Leslie CS, Marks DS | title = Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs | journal = Nature Biotechnology | volume = 27 | issue = 6 | pages = 549–55 | date = June 2009 | pmid = 19465925 | pmc = 2782465 | doi = 10.1038/nbt.1543 }}</ref> Thus, while siRNAs can produce unwanted off-target effects, i.e. unintended downregulation of mRNAs via a partial sequence match between the siRNA and target, the saturation of RNAi machinery is another distinct nonspecific effect, which involves the de-repression of miRNA-regulated genes and results in similar problems in data interpretation and potential toxicity.<ref>{{cite journal | vauthors = Grimm D, Streetz KL, Jopling CL, Storm TA, Pandey K, Davis CR, Marion P, Salazar F, Kay MA | display-authors = 6 | title = Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways | journal = Nature | volume = 441 | issue = 7092 | pages = 537–41 | date = May 2006 | pmid = 16724069 | doi = 10.1038/nature04791 | s2cid = 15118504 | bibcode = 2006Natur.441..537G }}</ref>