Let-7 microRNA family

Last updated
let-7 microRNA precursor
RF00027-rscape.svg
Predicted secondary structure and sequence conservation of let-7
Identifiers
Symbollet-7
Rfam RF00027
miRBase MI0000001
miRBase family MIPF0000002
Other data
RNA type Gene; miRNA
Domain(s) Eukaryota
GO GO:0035195 GO:0035068
SO SO:0001244
PDB structures PDBe

The Let-7 microRNA precursor gives rise to let-7, a microRNA (miRNA) involved in control of stem-cell division and differentiation [1] . let-7, short for "lethal-7", was discovered along with the miRNA lin-4 in a study of developmental timing in C. elegans [2] , making these miRNAs the first ever discovered. let-7 was later identified in humans as the first human miRNA , and is highly conserved across many species. [3] [4] Dysregulation of let-7 contributes to cancer development in humans by preventing differentiation of cells, leaving them stuck in a stem-cell like state. [1] let-7 is therefore classified as a tumor suppressor.

Contents

The let-7 microRNA family refers to the many slight variations of let-7 that exist both within a single organism and across species. In humans, for example, there are ten unique let-7 family member sequences: let-7a through g, let-7i, mir-98, and mir-202. [1]

In humans, mature let-7 acts via RNA-induced silencing by complexing with RISC and binding to target mRNA, preventing translation into protein. Known targets of let-7 include proteins related to the cell cycle and proliferation, such as MYC, RAS, cyclin D, HMGA2, and CDC25A. [1] Knockdown of these proteins by let-7 prevents proliferation and induces differentiation of cells. Important inhibitors of let-7 include LIN28, which binds to let-7 directly [5] , and the proto-oncogene MYC, which suppresses expression. [6]

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. [7]

The let-7 family

The lethal-7 (let-7) gene was first discovered in the nematode C. elegans as a key developmental regulator and became one of the first two known microRNAs (the other one is lin-4). [8] Soon, let-7 was found in the fruit fly (Drosophila), and identified as the first known human miRNA by a BLAST (basic local alignment search tool) research. [9] 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. [10] Among them, let-7, mir-84, mir-48 and mir-241 are involved in the C. elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions. [11] Most animals with loss-of-function let-7 mutation burst through their vulvas and die, and therefore the mutant is lethal (let). [8] 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. [12]

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. [13] 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. [14] 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. [15]

In vertebrates

The let-7 family has a lot more members in vertebrates than in C. elegans and Drosophila. [13] The sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species. [16] 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 temporally regulated during developmental processes. [17] Functionally, let-7 has been shown in early vertebrates to control the differentiation of mesoderm and ectoderm. [18] Given that the expression levels of let-7 members are significantly low in human cancers and cancer stem cells, [19] 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. [20] 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, [21] LIN28 expression is reciprocal to that of mature let-7. [5] LIN28 selectively binds the primary and precursor forms of let-7, and inhibits the processing of pri-let-7 to form the hairpin precursor. [22] This binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins. [23] Lin-28 uses two zinc knuckle domains to recognize the NGNNG motif in the let-7 precursors, [24] while the Cold-shock domain, connected by a flexible linker, binds to a closed loop in the precursors. [25] On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28, [26] which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator. [27]

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. [6] 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. [28] 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. [29]

Targets of let-7

Oncogenes: RAS, HMGA2

Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells [30] 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. [31] 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. [30] Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6 . [32] Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators. [30] Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation. [33]

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. [34] [35] 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 signaling and expression. [36] [37] 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. [38] 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. [39]

Potential clinical use in cancer

Given the prominent phenotype of cell overproliferation and dedifferentiation 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.

Prognostic Biomarkers

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. [7] 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. [40] In lung cancer, for example, reduced expression of let-7 is significantly correlated with reduced postoperative survival. [41] The expression of let-7b and let-7g microRNAs are significantly associated with overall survival in 1262 breast cancer patients. [42]

Therapy

Let-7 is also a very attractive potential therapeutic that can prevent tumorigenesis and angiogenesis, typically in cancers that underexpress let-7. [43] 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. [41] Intranasal administration of let-7 has already been found effective in reducing tumor growth in a transgenic mouse model of lung cancer. [44] Similar restoration of let-7 was also shown to inhibit cell proliferation in breast, colon and hepatic cancers, lymphoma, and uterine leiomyoma. [45]

Related Research Articles

microRNA Small non-coding ribonucleic acid molecule

Micro ribonucleic acid are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base-pair to complementary sequences in messenger RNA (mRNA) molecules, then silence said mRNA molecules by one or more of the following processes:

RNA activation (RNAa) is a small RNA-guided and Argonaute (Ago)-dependent gene regulation phenomenon in which promoter-targeted short double-stranded RNAs (dsRNAs) induce target gene expression at the transcriptional/epigenetic level. RNAa was first reported in a 2006 PNAS paper by Li et al. who also coined the term "RNAa" as a contrast to RNA interference (RNAi) to describe such gene activation phenomenon. dsRNAs that trigger RNAa have been termed small activating RNA (saRNA). Since the initial discovery of RNAa in human cells, many other groups have made similar observations in different mammalian species including human, non-human primates, rat and mice, plant and C. elegans, suggesting that RNAa is an evolutionarily conserved mechanism of gene regulation.

lin-4 microRNA precursor

In molecular biology lin-4 is a microRNA (miRNA) that was identified from a study of developmental timing in the nematode Caenorhabditis elegans. It was the first to be discovered of the miRNAs, a class of non-coding RNAs involved in gene regulation. miRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a 21 nucleotide product. The extents of the hairpin precursors are not generally known and are estimated based on hairpin prediction. The products are thought to have regulatory roles through complete or partial complementarity to mRNA. The lin-4 gene has been found to lie within a 4.11kb intron of a separate host gene.

mir-9/mir-79 microRNA precursor family

The miR-9 microRNA, is a short non-coding RNA gene involved in gene regulation. The mature ~21nt miRNAs are processed from hairpin precursor sequences by the Dicer enzyme. The dominant mature miRNA sequence is processed from the 5' arm of the mir-9 precursor, and from the 3' arm of the mir-79 precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In vertebrates, miR-9 is highly expressed in the brain, and is suggested to regulate neuronal differentiation. A number of specific targets of miR-9 have been proposed, including the transcription factor REST and its partner CoREST.

mir-129 microRNA precursor family

The miR-129 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. This microRNA was first experimentally characterised in mouse and homologues have since been discovered in several other species, such as humans, rats and zebrafish. The mature sequence is excised by the Dicer enzyme from the 5' arm of the hairpin. It was elucidated by Calin et al. that miR-129-1 is located in a fragile site region of the human genome near a specific site, FRA7H in chromosome 7q32, which is a site commonly deleted in many cancers. miR-129-2 is located in 11p11.2.

mir-17 microRNA precursor family

The miR-17 microRNA precursor family are a group of related small non-coding RNA genes called microRNAs that regulate gene expression. The microRNA precursor miR-17 family, includes miR-20a/b, miR-93, and miR-106a/b. With the exception of miR-93, these microRNAs are produced from several microRNA gene clusters, which apparently arose from a series of ancient evolutionary genetic duplication events, and also include members of the miR-19, and miR-25 families. These clusters are transcribed as long non-coding RNA transcripts that are processed to form ~70 nucleotide microRNA precursors, that are subsequently processed by the Dicer enzyme to give a ~22 nucleotide products. The mature microRNA products are thought to regulate expression levels of other genes through complementarity to the 3' UTR of specific target messenger RNA.

mir-1 microRNA precursor family Type of RNA

The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give products at ~22 nucleotides. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, and these are called miR-1-1 and miR-1-2.

mir-92 microRNA precursor family

The miR-92 microRNAs are short single stranded non-protein coding RNA fragments initially discovered incorporated into an RNP complex with a proposed role of processing RNA molecules and further RNP assembly. Mir-92 has been mapped to the human genome as part of a larger cluster at chromosome 13q31.3, where it is 22 nucleotides in length but exists in the genome as part of a longer precursor sequence. There is an exact replica of the mir-92 precursor on the X chromosome. MicroRNAs are endogenous triggers of the RNAi pathway which involves several ribonucleic proteins (RNPs) dedicated to repressing mRNA molecules via translation inhibition and/or induction of mRNA cleavage. miRNAs are themselves matured from their long RNA precursors by ribonucleic proteins as part of a 2 step biogenesis mechanism involving RNA polymerase 2.

<span class="mw-page-title-main">HMGA2</span> Protein-coding gene in the species Homo sapiens

High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.

<span class="mw-page-title-main">ERCC1</span> Protein-coding gene in the species Homo sapiens

DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.

<span class="mw-page-title-main">LIN28</span>

Lin-28 homolog A is a protein that in humans is encoded by the LIN28 gene.

<span class="mw-page-title-main">Victor Ambros</span> American developmental biologist (born 1953)

Victor R. Ambros is an American developmental biologist and Nobel Laureate who discovered the first known microRNA (miRNA). He is a professor at the University of Massachusetts Medical School. He completed both his undergraduate and doctoral studies at the Massachusetts Institute of Technology. Ambros received the Nobel Prize in Physiology or Medicine in 2024 for his research on microRNA.

<span class="mw-page-title-main">Gary Ruvkun</span> American geneticist (born 1952)

Gary Bruce Ruvkun is an American molecular biologist and Nobel laureate at Massachusetts General Hospital and professor of genetics at Harvard Medical School in Boston.

mir-145 Non-coding RNA in the species Homo sapiens

In molecular biology, mir-145 microRNA is a short RNA molecule that in humans is encoded by the MIR145 gene. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

mir-22

In molecular biology mir-22 microRNA is a short RNA molecule. MicroRNAs are an abundant class of molecules, approximately 22 nucleotides in length, which can post-transcriptionally regulate gene expression by binding to the 3' UTR of mRNAs expressed in a cell.

miR-138

miR-138 is a family of microRNA precursors found in animals, including humans. MicroRNAs are typically transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a ~22 nucleotide product. The excised region or, mature product, of the miR-138 precursor is the microRNA mir-138.

mir-48 microRNA is a microRNA which is found in nematodes, in which it controls developmental timing. It acts in the heterochronic pathway, where it controls the timing of cell fate decisions in the vulva and hypodermis during larval development.

In molecular biology mir-84 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

In molecular biology mir-241 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

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