Although the seed region of siRNA is implicated in the miRNAlike offtarget effect, only some mRNAs, with this type of sequence complementarity, are silenced by siRNA By analogy, miRNAs regulate the expression of multiple mRNAs through binding of the seed region to the target 3′UTR, but not all mRNAs with the same degree of sequence complementarity are the targets of a givenThe nonseed region of siRNA was found to be subdivided into four domains, in which two nucleotide pairs (positions 13 and 14) were replaceable with cognate deoxyribonucleotides without reducing RNAi activity However, RNA sequences at positions 912 and 1518 were essential for effective gene silencing,Signature transcript 39 UTRs contain sequence complementarity to siRNA seed regions The indicated siRNAs were transfected into HeLa cells Gene expression signatures (pvalue #
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Seed region sirna-MISSION ® Predesigned siRNA were created using the proprietary Rosetta Inpharmatics siRNA Design algorithm in an exclusive partnership with Merck & Co The Rosetta siRNA Design Algorithm utilizes PositionSpecific Scoring Matrices and knowledge of the seed region to predict the most specific and effective sequences for your target genes · Alternatively, siRNA could cause "partial offtarget" (seed matching offtarget) effects, in cases where the designed siRNA seeding region (second to seventh position) matches with 3′UTR of offtarget, affecting its translation
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· Asymmetric replacement of seed region nucleotides with DNA bases has also been shown to reduce offtargeting as a result of seed region complementarity within the passenger strand Recent in vitro studies have shown that shRNA produces fewer offtarget effects than siRNASilencer Select siRNA modifications reduce offtarget effects and yield more reliable phenotypic data New bioinformatics techniques to decipher real positives from false positives that arise from the seed region have been highlighted in this publicationSiDirect selects siRNAs with lower Tm value at the seed region, which contains 7 nucleotides at positions 28 from 5′ end of the guide strand siRNAs downregulate many unintended genes whose transcripts have complementarities to the siRNA seed region
However, the addition of a fifth condition of low thermodynamic stability in the seed region to the siRNA selection criteria (i)– (iv) decreased the percentage of selectable siRNA candidates fromThe primary source of siRNAmediated offtargets is the seed region (nucleotides 27), which uses the microRNA pathway to induce nonspecific gene silencing via interactions within the 3' UTR Incorporating comprehensive bioinformatic strategies such as seed region filters and seed frequency analysis within the SMARTselection design strategy minimizes microRNAlike offYuan et al, 05) Thus, the seed region first identifies the target mRNAs, and subsequently form perfect basepairing with intended target mRNA and induce RNAi by Ago2
· This region, specifically nucleotides 2–7 at the 5′ end of the miRNA strand, is considered the "seed region" (Lewis et al 05) mRNA complementarity to the 3′ region of a miRNA is not generally required for miRNA function, but it is likely that additional complementarity to this region results in enhanced miRNAmediated downregulationSize of seed region of siRNA we proposed is 68 bases Functional alignment Besides general sequence alignment, GenScript siRNA design tool incorporates a novel alignment approach, functional alignment This idea for functional aligment derives from asymmetry of siRNA in the assembly of the RNAi enzyme complexHence, its silencing effect has been assumed to be extremely specific However, accumulated evidences revealed that siRNA could downregulate unintended genes with partial complementarities mainly to the sevennucleotide seed region of siRNA This phenomenon is
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· Hence, because the siRNA seed region is a primary targetrecognition region, it is possible that the highly stable seedtarget duplex results in a strong siRNAWhen the siRNA seed region (2–8 nts from the 50 end of the guide strand) base pairs with the unintended genes 6–10 (Fig 1) The offtarget effect is considered to be induced by the similar molecular mechanismwithmiRNAmediatedRNAsilencing,whichdiffers from the mechanism of RNAiEnhance siRNA effectiveness Seed region filters and seed frequency analysis for siRNA designs to minimize offtarget effects ONTARGETplus modifications reduce the overall number of offtargets, and pooling reduces them even further Offtargets induced by the indicated siRNA
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· The siRNA seed–3′ UTR match is only one parameter in what is assumed to be an extremely complex phenomenon Because the sheer number of genes that contain matches with any given siRNA seed regionSeed sequence region c) Unexpected toxicity siRNA produces cell toxicity either through general activation of the innate immune response or by affecting offtarget genes with a role in cell viability Example Federov et al (06) reported sequencedependent cell · The seed region is known to be situated on the surface of Ago in a quasihelical form to serve as the entry or nucleation site for small RNAs in the RISCs (Ma et al, 05;
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Our results confirm previous reports that strength of basepairing in the siRNA seed region is the primary factor determining the efficiency of offtarget silencing However, the degree of downregulation of offtarget transcripts with shared seed sequence is not necessarily similar, suggesting that there are additional auxiliary factors that influence the silencing potentialThrough SeedPairing Thermal Destabilization Figure 3 Destabilization of seedpairing to minimize microRNAlike offtarget effects Incorporation of a thermally destabilizing modification into the seed region of the antisense strand (red nucleotide) can reduce binding to seedbased offtargets and therefore increase ontarget specificityWidespread siRNA ''offtarget'' transcript silencing mediated by seed region sequence complementarity AIMEE L JACKSON, JULJA BURCHARD, JANELL SCHELTER, B NELSON CHAU, MICHELE CLEARY,
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0214 · A highly functional siRNA may consist of two regions, the seed duplex region, which is capable of being totally replaced with DNA without substantial loss of gene silencing activity, and the nonseedduplex region, most of which should be RNA and possibly provide binding sites for RNAbinding RLC/RISC proteinsImportance of seed complement frequency to siRNA specificity RNA 14, 853–861 (08) Characterization of the microRNA seed region, nucleotides 2–6 of the siRNA antisense strand, predicts that nucleotide identity of this region may allow the siRNA to act through the microRNA pathway3–5 Thus, a negative controlRecognition of the mRNA target by RISC* occurs in several stages, wherein the "seed" region (the siRNA region from 2 to 8 nucleotides from the 5′ end of antisense strand) plays an important role
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To avoid off target effect, siRNA Wizard filter candidate siRNA sequence to remove sequence displaying a known miRNA SEED recognition region at 3' end Loop for short hairpin siRNAs (shRNA) We and others have tested a variety of sequences for the loop between the two complementary regions of a shRNA, ranging from 3 to 9 nt in length · Widespread siRNA "offtarget" transcript silencing mediated by seed region sequence complementarity Organism Homo sapiens Experiment type Expression profiling by array Summary Transfected siRNAs and miRNAs regulate numerous transcripts that have only limited complementarity to the active strand of the RNA duplexSmartBase TM siRNA Recommended Modifications 1 Alternating 2'F bases and 2'OMe bases in siRNA enhances duplex stability and are more resistant to RNase degradation 2 Use a few 2'OMe bases in the seed region of the guide strand to decrease the Tm below 215 of this region 2'O methyl base hybridization with RNA has a lower TM
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The seed region of siRNA guide strand and target mRNA (seedtarget duplex) (Figure 1a) 12 Furthermore, we have developed a DNARNA chimeric siRNA (chiRNA) with deoxyribonucleotides in the 5' proximal eight nucleotides of the guide strand and the complementary nucleotides The chiRNA showed virtually no offtarget effects,Seed region The chemical modifications of deoxyribonucleic acid (DNA), PS, and DNA−PS were introduced into all of the seven nucleotides of the seed region of the siRNA guide strand (Figure 2b) In addition, 3 (positions 4−6), 5 (positions 3−7),Silencer Select siRNA modifications reduce offtarget effects and yield more reliable phenotypic data New bioinformatics techniques to decipher real positives from false positives that arise from the seed region have been highlighted in this publication
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The siRNA Workflow A typical siRNA experiment (Figure 2) starts with the selection of a gene target and ends in the determination of knockdown efficiency, which is interpreted with respect to the objectives of the experimentFor studies that are focused on individual gene targets, there may be a variety of decisionmaking steps involved, as well as process optimization requirementsSiRNA recognition of the target mRNA is conferred by the "seed region", a six nucleotide stretch corresponding to positions 27 on the antisense siRNA strand After the siRNA seed region anneals, the catalytic RNase H domain of Argonaute then subjects perfectly complementary mRNA sequences 10 nucleotides from the 5' end of the incorporated siRNA strand to nucleolyticSeedbased offtarget effects A, seed region of Pik3ca siRNA B, cluster plots showing seeds enriched in 3' UTRs of downregulated genes after transfection with unmodified (B) or 2'Omethyl modified Pik3ca siRNA The "aaagcc"seed sequence remains enriched after chemical modification (Source Rasmussen et al,13)
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化学合成siRNA siRNA（small interfering RNA）とは、21～23塩基対からなる低分子二本鎖RNAです。 siRNAはRNAiと呼ばれる現象に関与しており、mRNAの切断によって配列特異的に遺伝子の発現を抑制します。 細胞内に導入されたsiRNAは、二本鎖のうちの一本鎖（アンチSelection of Chemical Modifications in the siRNA Seed Region That Repress OffTarget Effect Yoshiaki Kobayashi, Kengo Miyamoto, Misako Aida, Kumiko UiTei Pages 1730 StickBased Methods for AptamerMediated siRNA Targeted Delivery Silvia Catuogno, Carla Lucia Esposito, Paloma H GiangrandeCompared with an siRNAlike approach, the requirement of perfect complementarity of the microRNA seed region to a given target sequence in the microRNA/target model has proven to be a more efficient strategy, accomplishing the selective targeting of
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· Although littletono basepairing is usually observed between siRNA nonseed region (nucleotides 9– in Fig 1C) and the corresponding offtarget region, it was previously reported with miRNAs that such partial basepairing is an additional factor that influences the efficiency of seeddependent knockdown 18 , and was thus included in our analysisThe seed sequence or seed region is a conserved heptametrical sequence which is mostly situated at positions 27 from the miRNA 5´end Even though base pairing of miRNA and its target mRNA does not match perfect, the "seed sequence" has to be perfectly complementary · Clearly, the seed sequences of miRNA (identified with miRNA databases) should be avoided in siRNA design 69 In addition, the siRNA should have a low thermodynamic stability of the duplex between the seed region of the guide strand of siRNA and its target mRNA, since a low seedtarget duplex stability reduces the capability of siRNA to induce seeddependent off
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1910 · 3' UTR/seed region analysis Several studies have shown that offtarget effects may be caused by matches of the seed region of the siRNA antisense strand with the 3' untranslated region of unintended mRNA targets (see table) The seed region comprises 6 nucleotides in positions 2–7 of the antisense siRNA strand of the siRNA duplex · siRNA seed regions preferentially align with the 3′ UTR regions of unintended transcripts (Upper panels) 36 siRNAs were aligned by FASTA to their downregulated offtarget signature transcripts and to a background set of 10,631 transcript sequences with mapped CDS · Such offtarget effect is an undesirable adverse effect for knocking down a target gene specifically Here we describe the powerful strategy to avoid offtarget effects without affecting the RNAi activity by the introduction of DNA or 2′Omethyl modifications in the siRNA seed region
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SiRNA designs with lowfrequency seed regions ensure fewer offtargets SMARTpool siRNA reagents improve specificity when retaining high potency 5' 3' 3' 5' Antisense Strand Sense Strand seed region of antisense strand (positions 27) 100 80 60 40 0 Low Medium High Seed Frequency Class Number of OffTargets
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