MicroRNA-Directed Cleavage of HOXB8 mRNA

MicroRNAs (miRNAs) are endogenous ∼22-nucleotide RNAs, some of which are known to play important regulatory roles in animals by targeting the messages of protein-coding genes for translational repression. We find that miR-196, a miRNA encoded at three paralogous locations in the A, B, and C mammalian HOX clusters, has extensive, evolutionarily conserved complementarity to messages of HOXB8, HOXC8, and HOXD8. RNA fragments diagnostic of miR-196–directed cleavage of HOXB8 were detected in mouse embryos. Cell culture experiments demonstrated down-regulation of HOXB8, HOXC8, HOXD8, and HOXA7 and supported the cleavage mechanism for miR-196–directed repression of HOXB8. These results point to a miRNA-mediated mechanism for the posttranscriptional restriction of HOX gene expression during vertebrate development and demonstrate that metazoan miRNAs can repress expression of their natural targets through mRNA cleavage in addition to inhibiting productive translation.

[1]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[2]  John G Doench,et al.  Specificity of microRNA target selection in translational repression. , 2004, Genes & development.

[3]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[4]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[5]  Hajime Sakai,et al.  Regulation of Flowering Time and Floral Organ Identity by a MicroRNA and Its APETALA2-Like Target Genes Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.016238. , 2003, The Plant Cell Online.

[6]  Julius Brennecke,et al.  Identification of Drosophila MicroRNA Targets , 2003, PLoS biology.

[7]  B. Cullen,et al.  MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Marks,et al.  The small RNA profile during Drosophila melanogaster development. , 2003, Developmental cell.

[9]  D. Duboule,et al.  Organizing Axes in Time and Space; 25 Years of Colinear Tinkering , 2003, Science.

[10]  P. Rigby,et al.  Multiple levels of transcriptional and post-transcriptional regulation are required to define the domain of Hoxb4 expression , 2003, Development.

[11]  B. Li,et al.  Expression profiling reveals off-target gene regulation by RNAi , 2003, Nature Biotechnology.

[12]  C. Burge,et al.  The microRNAs of Caenorhabditis elegans. , 2003, Genes & development.

[13]  C. Burge,et al.  Vertebrate MicroRNA Genes , 2003, Science.

[14]  Phillip A Sharp,et al.  siRNAs can function as miRNAs , 2003 .

[15]  Edwards Allen,et al.  P1/HC-Pro, a viral suppressor of RNA silencing, interferes with Arabidopsis development and miRNA unction. , 2003, Developmental cell.

[16]  T. Tuschl,et al.  New microRNAs from mouse and human. , 2003, RNA.

[17]  B. Reinhart,et al.  A biochemical framework for RNA silencing in plants. , 2003, Genes & development.

[18]  C. Llave,et al.  Cleavage of Scarecrow-like mRNA Targets Directed by a Class of Arabidopsis miRNA , 2002, Science.

[19]  G. Hutvagner,et al.  A microRNA in a Multiple-Turnover RNAi Enzyme Complex , 2002, Science.

[20]  Eric J Wagner,et al.  Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells. , 2002, Molecular cell.

[21]  E. Moss,et al.  Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation. , 2002, Developmental biology.

[22]  V. Ambros,et al.  The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. , 1999, Developmental biology.

[23]  C. Tabin,et al.  Analysis of Hox gene expression in the chick limb bud. , 1996, Development.

[24]  A. Mccarthy Development , 1996, Current Opinion in Neurobiology.

[25]  R. Krumlauf Hox genes in vertebrate development , 1994, Cell.