An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans

doi:10.1126/SCIENCE.1065062

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An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans

Journal Article•DOI•

An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans

Nelson C. Lau¹, Lee P. Lim¹, Earl G. Weinstein¹, David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

26 Oct 2001-Science (American Association for the Advancement of Science)-Vol. 294, Iss: 5543, pp 858-862

TL;DR: Two small temporal RNAs, lin-4 andlet-7, control developmental timing in Caenorhabditis elegans and are found to be members of a large class of 21- to 24-nucleotide noncodingRNAs, called microRNAs (miRNAs), which imply that, as a class, miRNAs have broad regulatory functions in animals.

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Abstract: Two small temporal RNAs (stRNAs), lin-4 and let-7, control developmental timing in Caenorhabditis elegans. We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans. The miRNAs have diverse expression patterns during development: a let-7 paralog is temporally coexpressed with let-7; miRNAs encoded in a single genomic cluster are coexpressed during embryogenesis; and still other miRNAs are expressed constitutively throughout development. Potential orthologs of several of these miRNA genes were identified in Drosophila and human genomes. The abundance of these tiny RNAs, their expression patterns, and their evolutionary conservation imply that, as a class, miRNAs have broad regulatory functions in animals.

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Journal Article•DOI•

MicroRNAs: Genomics, Biogenesis, Mechanism, and Function

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David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

23 Jan 2004-Cell

TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

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32,946 citations

Cites background or methods from "An Abundant Class of Tiny RNAs with..."

...Extrapolat- of the plant miRNAs (Lau et al., 2001; Reinhart et al., ing from this sensitivity and the number of additional 2002; Bartel and Bartel, 2003)....
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...Like C. elegans lin-4 and let-7, most miRNA genes scription as a multi-cistronic primary transcript (LagosQuintana et al., 2001; Lau et al., 2001)....
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...…has four identified members in C. elegans and at logs of known miRNA genes (Pasquinelli et al., 2000; least 15 in human, but only one in Drosophila (Pasquinelli Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and et al., 2000; Aravin et al., 2003; Lai et al., 2003; Lim et Ambros, 2001)....
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...…that they derive majority of worm and human miRNA genes are isolated and not clustered (Lim et al., 2003a, 2003b), over halffrom independent transcription units (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001). of the known Drosophila miRNAs are clustered (Aravin et al., 2003)....
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...Shown are the C. elegans stem loops, but close homologs of these miRNAs have been found in flies and mammals (Lagos-Quintana et al., 2001, 2002; Lau et al., 2001; Lee and Ambros, 2001)....
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Journal Article•DOI•

MicroRNAs: Target Recognition and Regulatory Functions

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David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

23 Jan 2009-Cell

TL;DR: The current understanding of miRNA target recognition in animals is outlined and the widespread impact of miRNAs on both the expression and evolution of protein-coding genes is discussed.

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18,036 citations

Cites background from "An Abundant Class of Tiny RNAs with..."

...…RNAs found in worms, flies and mammals—a few expressed temporally, but most not—which were named microRNAs (miRNAs) (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001). miRNAs have since been found in plants, green algae, viruses, and more deeply branching animals…...
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...Soon thereafter, lin-4 and let-7 RNAs were reported to represent a very populous class of small endogenous RNAs found in worms, flies and mammals—a few expressed temporally, but most not—which were named microRNAs (miRNAs) (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001)....
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...An answer to this question becomes apparent when considering the other let-7 family members in worms, which include let-7, miR-48, miR-84, and miR-241, all of which have the same seed region but differ in their remaining sequence (Lau et al., 2001; Lim et al., 2003)....
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Journal Article•DOI•

Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets

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Benjamin P. Lewis¹, Christopher B. Burge¹, David P. Bartel¹•Institutions (1)

Massachusetts Institute of Technology¹

14 Jan 2005-Cell

TL;DR: In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of the gene set.

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11,624 citations

Additional excerpts

...(Lau et al., 2001)....
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Journal Article•DOI•

The functions of animal microRNAs

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Victor R. Ambros¹•Institutions (1)

Dartmouth College¹

15 Sep 2004-Nature

TL;DR: Evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.

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Abstract: MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.

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9,986 citations

Journal Article•DOI•

MicroRNA expression profiles classify human cancers

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Jun Lu¹, Gad Getz¹, Eric A. Miska², Eric A. Miska³, Ezequiel Alvarez-Saavedra², Justin Lamb¹, David Peck¹, Alejandro Sweet-Cordero⁴, Alejandro Sweet-Cordero², Benjamin L. Ebert⁴, Benjamin L. Ebert¹, Raymond H. Mak⁴, Raymond H. Mak¹, Adolfo A. Ferrando⁴, James R. Downing⁵, Tyler Jacks², H. Robert Horvitz⁶, H. Robert Horvitz², Todd R. Golub⁶, Todd R. Golub⁴, Todd R. Golub¹ - Show less +17 more•Institutions (6)

Broad Institute¹, Massachusetts Institute of Technology², Wellcome Trust/Cancer Research UK Gurdon Institute³, Harvard University⁴, St. Jude Children's Research Hospital⁵, Howard Hughes Medical Institute⁶

09 Jun 2005-Nature

TL;DR: A new, bead-based flow cytometric miRNA expression profiling method is used to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers, and finds the miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours.

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Abstract: Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.

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9,470 citations

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References

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Journal Article•DOI•

The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

[...]

Rosalind C. Lee¹, Rhonda L. Feinbaum¹, Victor R. Ambros¹•Institutions (1)

Harvard University¹

03 Dec 1993-Cell

TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.

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11,932 citations

Journal Article•DOI•

Role for a bidentate ribonuclease in the initiation step of RNA interference

[...]

Emily Bernstein¹, Amy A. Caudy², Amy A. Caudy¹, Scott Hammond¹, Gregory J. Hannon¹ - Show less +1 more•Institutions (2)

Cold Spring Harbor Laboratory¹, Watson School of Biological Sciences²

18 Jan 2001-Nature

TL;DR: Dicer is a member of the RNase III family of nucleases that specifically cleave double-stranded RNAs, and is evolutionarily conserved in worms, flies, plants, fungi and mammals, and has a distinctive structure, which includes a helicase domain and dualRNase III motifs.

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Abstract: RNA interference (RNAi) is the mechanism through which double-stranded RNAs silence cognate genes. In plants, this can occur at both the transcriptional and the post-transcriptional levels; however, in animals, only post-transcriptional RNAi has been reported to date. In both plants and animals, RNAi is characterized by the presence of RNAs of about 22 nucleotides in length that are homologous to the gene that is being suppressed. These 22-nucleotide sequences serve as guide sequences that instruct a multicomponent nuclease, RISC, to destroy specific messenger RNAs. Here we identify an enzyme, Dicer, which can produce putative guide RNAs. Dicer is a member of the RNase III family of nucleases that specifically cleave double-stranded RNAs, and is evolutionarily conserved in worms, flies, plants, fungi and mammals. The enzyme has a distinctive structure, which includes a helicase domain and dual RNase III motifs. Dicer also contains a region of homology to the RDE1/QDE2/ARGONAUTE family that has been genetically linked to RNAi.

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5,229 citations

Journal Article•DOI•

The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

[...]

Brenda J. Reinhart¹, Frank J. Slack², Frank J. Slack¹, Michael Basson³, Amy E. Pasquinelli¹, Bettinger Jc⁴, Ann E. Rougvie⁵, H R Horvitz³, Gary Ruvkun¹ - Show less +5 more•Institutions (5)

Harvard University¹, Yale University², Massachusetts Institute of Technology³, University of California, San Francisco⁴, University of Minnesota⁵

24 Feb 2000-Nature

TL;DR: It is shown that let-7 is a heterochronic switch gene that encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heteroch chronic genes lin-14, lin-28, Lin-41, lin -42 and daf-12, indicating that expression of these genes may be directly controlled by let- 7.

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Abstract: The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events1. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated2. Here we show that let-7 is a heterochronic switch gene. Loss of let-7 gene activity causes reiteration of larval cell fates during the adult stage, whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indicating that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3′ untranslated region is temporally regulated in a let-7-dependent manner. A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA–RNA interactions with their 3′ untranslated regions3,4. We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing.

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4,821 citations

Journal Article•DOI•

Identification of novel genes coding for small expressed RNAs.

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Mariana Lagos-Quintana¹, Reinhard Rauhut¹, Winfried Lendeckel¹, Thomas Tuschl¹•Institutions (1)

Max Planck Society¹

26 Oct 2001-Science

TL;DR: It is shown that many 21- and 22-nt expressed RNAs, termed microRNAs, exist in invertebrates and vertebrates and that some of these novel RNAs are highly conserved, which suggests that sequence-specific, posttranscriptional regulatory mechanisms mediated by smallRNAs are more general than previously appreciated.

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Abstract: In Caenorhabditis elegans, lin-4 and let-7 encode 22- and 21-nucleotide (nt) RNAs, respectively, which function as key regulators of developmental timing. Because the appearance of these short RNAs is regulated during development, they are also referred to as small temporal RNAs (stRNAs). We show that many 21- and 22-nt expressed RNAs, termed microRNAs, exist in invertebrates and vertebrates and that some of these novel RNAs, similar to let-7 stRNA, are highly conserved. This suggests that sequence-specific, posttranscriptional regulatory mechanisms mediated by small RNAs are more general than previously appreciated.

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4,484 citations

Journal Article•DOI•

Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans

[...]

Bruce Wightman¹, Ilho Ha¹, Gary Ruvkun¹•Institutions (1)

Harvard University¹

03 Dec 1993-Cell

TL;DR: It is demonstrated that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4.

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4,084 citations