Biology:let-7 microRNA precursor

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let-7 microRNA precursor
RF00027-rscape.svg
Predicted secondary structure and sequence conservation of let-7
Identifiers
Symbollet-7
RfamRF00027
miRBaseMI0000001
miRBase familyMIPF0000002
Other data
RNA typeGene; miRNA
Domain(s)Eukaryota
GO0035195 0035068
SO0001244
PDB structuresPDBe

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans,[1] and was later shown to be part of a much larger class of non-coding RNAs termed microRNAs.[2] miR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been predicted or experimentally confirmed in a wide range of species (MIPF0000002[3]). miRNAs are initially transcribed in long transcripts (up to several hundred nucleotides) called primary miRNAs (pri-miRNAs), which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide. These precursors (pre-miRNAs) are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference.

Genomic Locations

In human genome, the cluster let-7a-1/let-7f-1/let-7d is inside the region B at 9q22.3, with the defining marker D9S280-D9S1809. One minimal LOH (loss of heterozygosity) region, between loci D11S1345-D11S1316, contains the cluster miR-125b1/let-7a-2/miR-100. The cluster miR-99a/let-7c/miR-125b-2 is in a 21p11.1 region of HD (homozygous deletions). The cluster let-7g/miR-135-1 is in region 3 at 3p21.1-p21.2.[4]

The let-7 family

The lethal-7 (let-7) gene was first discovered in the nematode as a key developmental regulator and became one of the first two known microRNAs (the other one is lin-4).[5] Soon, let-7 was found in fruit fly, and identified as the first known human miRNA by a BLAST (basic local alignment search tool) research.[6] The mature form of let-7 family members is highly conserved across species.

In C.elegans

In C.elegans, the let-7 family consists of genes encoding nine miRNAs sharing the same seed sequence.[7] Among them, let-7, mir-84, mir-48 and mir-241 are involved in C.elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions.[8] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let).[5] The mutants of other let-7 family members have a radio-resistant phenotype in vulval cells, which may be related to their ability to repress RAS.[9]

In Drosophila

There is only one single let-7 gene in the Drosophila genome, which has the identical mature sequence to the one in C.elegans.[10] The role of let-7 has been demonstrated in regulating the timing of neuromuscular junction formation in the abdomen and cell-cycle in the wing.[11] Furthermore, the expression of pri-, pre- and mature let-7 have the same rhythmic pattern with the hormone pulse before each cuticular molt in Drosophila.[12]

In vertebrates

The let-7 family has a lot more members in vertebrates than in C.elegans and Drosophila.[10] The sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species.[13] The direct role of let-7 family in vertebrate development has not been clearly shown as in less complex organisms, yet the expression pattern of let-7 family is indeed temporal during developmental processes.[14] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells,[15] the major function of let-7 genes may be to promote terminal differentiation in development and tumor suppression.

Regulation of expression

Although the levels of mature let-7 members are undetectable in undifferentiated cells, the primary transcripts and the hairpin precursors of let-7 are present in these cells.[16] It indicates that the mature let-7 miRNAs may be regulated in a post-transcriptional manner.

By pluripotency promoting factor LIN28

As one of the genes involved in (but not essential for) induced pluripotent stem (iPS) cell reprogramming,[17] LIN28 expression is reciprocal to that of mature let-7.[18] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor.[19] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins.[20] Lin-28 uses two zinc knuckle domains to recognize the NGNNG motif in the let-7 precursors,[21] while the Cold-shock domain, connected by a flexible linker, binds to a closed loop in the precursors.[22] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28,[23] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator.[24]

In autoregulatory loop with MYC

Expression of let-7 members is controlled by MYC binding to their promoters. The levels of let-7 have been reported to decrease in models of MYC-mediated tumorigenesis, and to increase when MYC is inhibited by chemicals.[25] In a twist, there are let-7-binding sites in MYC 3' untranslated region(UTR) according to bioinformatic analysis, and let-7 overexpression in cell culture decreased MYC mRNA levels.[26] Therefore, there is a double-negative feedback loop between MYC and let-7. Furthermore, let-7 could lead to IMP1(/insulin-like growth factor II mRNA-binding protein) depletion, which destabilizes MYC mRNA, thus forming an indirect regulatory pathway.[27]

Targets of let-7

Oncogenes: RAS, HMGA2

Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells[28] All the three RAS genes in human, K-, N-, and H-, have the predicted let-7 binding sequences in their 3'UTRs. In lung cancer patient samples, expression of RAS and let-7 showed reciprocal pattern, which has low let-7 and high RAS in cancerous cells, and high let-7 and low RAS in normal cells. Another oncogene, high mobility group A2 (HMGA2), has also been identified as a target of let-7. Let-7 directly inhibits HMGA2 by binding to its 3'UTR.[29] Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor.

Cell cycle, proliferation, and apoptosis regulators

Microarray analyses revealed many genes regulating cell cycle and cell proliferation that are responsive to alteration of let-7 levels, including cyclin A2, CDC34, Aurora A and B kinases (STK6 and STK12), E2F5, and CDK8, among others.[28] Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6.[30] Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators.[28] Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation.[31]

Immunity

Let-7 has been implicated in post-transcriptional control of innate immune responses to pathogenic agents. Macrophages stimulated with live bacteria or purified microbial components down-regulate the expression of several members of the let-7 microRNA family to relieve repression of immune-modulatory cytokines IL-6 and IL-10.[32][33] Let-7 has also been implicated in the negative regulation of TLR4, the major immune receptor of microbial lipopolysaccharide and down-regulation of let-7 both upon microbial and protozoan infection might elevate TLR4 signalling and expression.[34][35] Let-7 has furthermore been reported to regulate the production of cytokine IL-13 by T lymphocytes during allergic airway inflammation thus linking this microRNA to adaptive immunity as well.[36] Down-modulation of let-7 negative regulator Lin28b in human T lymphocytes is believed to accrue during early neonate development to reprogram the immune system towards defense.[37]

Potential clinical use in cancer

Given the prominent phenotype of cell overproliferation and undifferentiation by let-7 loss-of-function in nematodes, and the role of its targets on cell destiny determination, let-7 is closely associated with human cancer and acts as a tumor suppressor.

Diagnosis

Numerous reports have shown that the expression levels of let-7 are frequently low and the chromosomal clusters of let-7 are often deleted in many cancers.[4] Let-7 is expressed at higher levels in more differentiated tumors, which also have lower levels of activated oncogenes such as RAS and HMGA2. Therefore, expression levels of let-7 could be prognostic markers in several cancers associated with differentiation stages.[38] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival.[39] The expression of let-7b and let-7g microRNAs are significantly associated with overall survival in 1262 breast cancer patients.[40]

Therapy

Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7.[41] Lung cancer, for instance, has several key oncogenic mutations including p53, RAS and MYC, some of which may directly correlate with the reduced expression of let-7, and may be repressed by introduction of let-7.[39] Intranasal administration of let-7 has already been found effective in reducing tumor growth in a transgenic mouse model of lung cancer.[42] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma.[43]

References

  1. ↑ Rougvie, AE (2001). "Control of developmental timing in animals". Nature Reviews Genetics 2 (9): 690–701. doi:10.1038/35088566. PMID 11533718. 
  2. ↑ Ambros, V (2001). "microRNAs: tiny regulators with great potential". Cell 107 (7): 823–826. doi:10.1016/S0092-8674(01)00616-X. PMID 11779458. 
  3. ↑ MIPF0000002
  4. ↑ 4.0 4.1 Calin; Sevignani, C; Dumitru, CD; Hyslop, T; Noch, E; Yendamuri, S; Shimizu, M; Rattan, S et al. (2003). "Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers". PNAS 101 (9): 2999–3004. doi:10.1073/pnas.0307323101. PMID 14973191. Bibcode: 2004PNAS..101.2999C. 
  5. ↑ 5.0 5.1 Reinhart B.J. et al. (2000). "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans". Nature 403 (6772): 901–906. doi:10.1038/35002607. PMID 10706289. Bibcode: 2000Natur.403..901R. 
  6. ↑ Pasquinelli A.E. (2000). "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA". Nature 408 (6808): 86–89. doi:10.1038/35040556. PMID 11081512. Bibcode: 2000Natur.408...86P. 
  7. ↑ Lim L.P. (2003). "The microRNAs of Caenorhabditis elegans". Genes Dev 17 (8): 991–1008. doi:10.1101/gad.1074403. PMID 12672692. 
  8. ↑ Moss E.G. (2007). "Heterochronic genes and the nature of developmental time". Curr. Biol. 17 (11): R425–R434. doi:10.1016/j.cub.2007.03.043. PMID 17550772. 
  9. ↑ Weidhaas J.B. (2007). "MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy". Cancer Res. 67 (23): 11111–11116. doi:10.1158/0008-5472.CAN-07-2858. PMID 18056433. 
  10. ↑ 10.0 10.1 Lagos-Quintana M. et al. (2001). "Identification of novel genes coding for small expressed RNAs". Science 294 (5543): 853–858. doi:10.1126/science.1064921. PMID 11679670. Bibcode: 2001Sci...294..853L. 
  11. ↑ Caygill E.E.; Johnston L.A. (2008). "Temporal Regulation of Metamorphic Processes in Drosophila by the let-7 and miR-125 Heterochronic MicroRNAs". Curr. Biol. 18 (13): 943–950. doi:10.1016/j.cub.2008.06.020. PMID 18571409. 
  12. ↑ Thummel C.S. (2001). "Molecular mechanisms of developmental timing in C. elegans and Drosophila". Dev. Cell 1 (4): 453–465. doi:10.1016/S1534-5807(01)00060-0. PMID 11703937. 
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  16. ↑ Thomson J.M. (2006). "Extensive post-transcriptional regulation of microRNAs and its implications for cancer". Genes Dev. 20 (16): 2202–2207. doi:10.1101/gad.1444406. PMID 16882971. 
  17. ↑ Yu J. et al. (2007). "Induced pluripotent stem cell lines derived from human somatic cells". Science 318 (5858): 1917–1920. doi:10.1126/science.1151526. PMID 18029452. Bibcode: 2007Sci...318.1917Y. 
  18. ↑ Viswanathan S.R. et al. (2008). "Selective blockade of microRNA processing by Lin-28". Science 320 (5872): 97–100. doi:10.1126/science.1154040. PMID 18292307. Bibcode: 2008Sci...320...97V. 
  19. ↑ Newman M.A. (2008). "Lin-28 interaction with the let-7 precursor loop mediates regulated microRNA processing". RNA 14 (8): 1539–49. doi:10.1261/rna.1155108. PMID 18566191. 
  20. ↑ Piskounova E. (2008). "Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28". J. Biol. Chem. 283 (31): 21310–21314. doi:10.1074/jbc.C800108200. PMID 18550544. 
  21. ↑ Loughlin, Fionna E; Gebert, Luca F R; Towbin, Harry; Brunschweiger, Andreas; Hall, Jonathan; Allain, Frédéric H-T (11 December 2011). "Structural basis of pre-let-7 miRNA recognition by the zinc knuckles of pluripotency factor Lin28". Nature Structural & Molecular Biology 19 (1): 84–89. doi:10.1038/nsmb.2202. PMID 22157959. 
  22. ↑ Nam, Yunsun; Chen, Casandra; Gregory, Richard I.; Chou, James J.; Sliz, Piotr (November 2011). "Molecular Basis for Interaction of let-7 MicroRNAs with Lin28". Cell 147 (5): 1080–1091. doi:10.1016/j.cell.2011.10.020. PMID 22078496. 
  23. ↑ Moss E.G.; Tang L. (2003). "Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites". Dev. Biol. 258 (2): 432–442. doi:10.1016/S0012-1606(03)00126-X. PMID 12798299. 
  24. ↑ Ali, P. S.; Ghoshdastider, U; Hoffmann, J; Brutschy, B; Filipek, S (2012). "Recognition of the let-7g miRNA precursor by human Lin28B". FEBS Letters 586 (22): 3986–90. doi:10.1016/j.febslet.2012.09.034. PMID 23063642. 
  25. ↑ Chang T.C. (2007). "Widespread microRNA repression by Myc contributes to tumorigenesis". Nat. Genet. 40 (1): 43–50. doi:10.1038/ng.2007.30. PMID 18066065. 
  26. ↑ Koscianska E. et al. (2007). "Prediction and preliminary validation of oncogene regulation by miRNAs". BMC Mol. Biol. 8: 79. doi:10.1186/1471-2199-8-79. PMID 17877811. 
  27. ↑ Ioannidis P. (2005). "CRD-BP/IMP1 expression characterizes cord blood CD34+ stem cells and affects c-myc and IGF-II expression in MCF-7 cancer cells". J. Biol. Chem. 280 (20): 20086–20093. doi:10.1074/jbc.M410036200. PMID 15769738. 
  28. ↑ 28.0 28.1 28.2 "RAS is regulated by the let-7 microRNA family". Cell 120 (5): 635–47. 2005. doi:10.1016/j.cell.2005.01.014. PMID 15766527. 
  29. ↑ Mayr C. et al. (2007). "Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation". Science 315 (5818): 1576–1579. doi:10.1126/science.1137999. PMID 17322030. Bibcode: 2007Sci...315.1576M. 
  30. ↑ Johnson C.D. (2007). "The let-7 microRNA represses cell proliferation pathways in human cells". Cancer Res. 67 (16): 7713–7722. doi:10.1158/0008-5472.CAN-07-1083. PMID 17699775. 
  31. ↑ He YJ, Guo L, D ZH. (2009) Let-7 and mir-24 in uvb-induced apoptosis [Chinese]. Zhonghua Fang She Yi Xue Yu Fang Hu Za Zhi. 29, 234–6.
  32. ↑ Schulte LN (2011). "Analysis of the host miRNA response to Salmonella uncovers the control of major cytokines by the let-7 family". The EMBO Journal 30 (10): 1977–1989. doi:10.1038/emboj.2011.94. PMID 21468030. 
  33. ↑ Liu Y (2011). "MicroRNA-98 negatively regulates IL-10 production and endotoxin tolerance in macrophages after LPS stimulation". FEBS Letters 585 (12): 1963–1968. doi:10.1016/j.febslet.2011.05.029. PMID 21609717. 
  34. ↑ Hu G (2009). "MicroRNA-98 and let-7 Confer Cholangiocyte Expression of Cytokine-Inducible Src Homology 2-Containing Protein in Response to Microbial Challenge". The Journal of Immunology 183 (3): 1617–1624. doi:10.4049/jimmunol.0804362. PMID 19592657. 
  35. ↑ Androulidaki A (2009). "Akt1 controls macrophage response to LPS by regulating microRNAs". Immunity 31 (2): 220–231. doi:10.1016/j.immuni.2009.06.024. PMID 19699171. 
  36. ↑ Kumar M (2011). "Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation". The Journal of Allergy and Clinical Immunology 128 (5): 1077–1085. doi:10.1016/j.jaci.2011.04.034. PMID 21616524. 
  37. ↑ Yuan J et al. (2012). "Lin28b Reprograms Adult Bone Marrow Hematopoietic Progenitors to Mediate Fetal-Like Lymphopoiesis". Science 335 (6073): 1195–12000. doi:10.1126/science.1216557. PMID 22345399. Bibcode: 2012Sci...335.1195Y. 
  38. ↑ Shell S; Park SM; Radjabi AR et al. (2007). "Let-7 expression defines two differentiation stages of cancer". Proc Natl Acad Sci U S A 104 (27): 11400–5. doi:10.1073/pnas.0704372104. PMID 17600087. Bibcode: 2007PNAS..10411400S. 
  39. ↑ 39.0 39.1 Takamizawa JExpression error: Unrecognized word "etal". (2004). "Reduced expression of the let-7 micrornas in human lung cancers in association with shortened postoperative survival". Cancer Res. 64 (11): 3753–6. doi:10.1158/0008-5472.CAN-04-0637. PMID 15172979. 
  40. ↑ Lánczky, András; Nagy, Ádám; Bottai, Giulia; Munkácsy, Gyöngyi; Szabó, András; Santarpia, Libero; Győrffy, Balázs (2016-12-01). "miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients". Breast Cancer Research and Treatment 160 (3): 439–446. doi:10.1007/s10549-016-4013-7. ISSN 1573-7217. PMID 27744485. 
  41. ↑ "Role of Dicer and Drosha for endothelial microrna expression and angiogenesis". Circ Res 101 (1): 59–68. 2007. doi:10.1161/CIRCRESAHA.107.153916. PMID 17540974. 
  42. ↑ EsquelaExpression error: Unrecognized word "etal". (2008). "The let-7 microrna reduces tumor growth in mouse models of lung cancer". Cell Cycle 7 (6): 759–64. doi:10.4161/cc.7.6.5834. PMID 18344688. 
  43. ↑ Barh D.; Malhotra R.; Ravi B.; Sindhurani P. (2010). "MicroRNA let-7: an emerging next-generation cancer therapeutic". Current Oncology 17 (1): 70–80. doi:10.3747/co.v17i1.356. PMID 20179807. 

Further reading

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