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Molecular genetics of mammalian microRNAs
The fundamental aim of our research is to define the in vivo roles of mammalian microRNAs (miRNAs). To achieve this goal, we combine the
classical methods of mouse genetics and molecular biology with modern genomics, and bioinformatics technologies. miRNAs are a class of 22-nucleotide, short,
noncoding RNAs which regulate gene expression through sequence-specific base pairing within target mRNAs. With well over 500 members per species in mammals, miRNAs
are one of the largest gene families, and account for ~2% genes in the genome but very little is known about their function.
Our previous analysis of a mouse germline miRNA knockout, miR-155, revealed an essential role for this miRNA in humoral immunity and B & T lymphocyte
function. More generally, this work established that individual miRNAs are of key physiological importance in mammals.
- Physiological role of the let-7 miRNA
lethal-7 (let-7) is one of the founding members of the miRNA family initially identified in C. elegans as a factor involved in the regulation of
developmental timing. let-7 is a key gene in the ‘heterochronic’ pathways which govern how tissues and organs are specified at the correct time
and synchronized during C. elegans development. let-7 is highly conserved in sequence in multicellular animals and by analogy to C. elegans, is also temporally
expressed in vertebrates. In mammals, twelve homologous let-7 genes are present in the genome and dispersed on seven different chromosomes making their analysis challenging.
A role for mammalian let-7 family in the pathophysiology of cancer, is suggested by frequent loss of expression in lung, breast cancer as well as other tumor
types. Mechanistically, let-7 has been shown to inhibit the proliferation of mammalian cells in vitro and affect the expression of genes involved in the cell cycle
progression and cell growth. However very little is known about the physiologic function(s) of let-7 in mammals.
My lab is particularly interested in defining the function of let-7. To this end, let-7 knockout mice have been generated using embryonic stem (ES) cell
targeting technology and being used as tools to explore the critical role of let-7 in embryonic and postnatal development. We are also investigating how let-7
reprograms cells, tissues and organs during the fetal-to-adult transition and impacts on cell "stemness", aging, and cancer.
- microRNA "targetomics" and disease networks
A secondary long-term goal of our lab is to discover the circuitry or network of posttranscriptional gene silencing by mammalian miRNAs. The extent
and scope of genes inhibited by miRNAs are only now beginning to be understood. One of the key first steps towards dissecting functions of miRNAs is to identity the full
complement of genes under-miRNA control. For example, we identified Pu.1 and c-Maf as key direct targets of miR-155 in B and T cells respectively by microarray analysis.
We make use of microarrays and biochemical methods to reveal the key circuitry or "targetomes" of miRNAs in diverse cells. At present, we are focusing on a single miRNA,
which regulates numerous genes associated with metabolic syndrome.
Selected Publications
Rodriguez A, Zhou Z, Tang ML, Meller S, Chen J, Bellen H, Kimbrell DA (1996) Identification of immune system and response genes, and novel
mutations causing melanotic tumor formation in Drosophila melanogaster. Genetics 143:929-940.
Rodriguez A, Oliver H, Zou H, Chen P, Wang X, Abrams JM (1999) Dark is a Drosophila homologue of Apaf-1/CED-4 and functions in an evolutionarily
conserved death pathway. Nature Cell Biology 1:272-279.
Leulier F, Rodriguez A, Khush RS, Abrams JM, Lemaitre B (2000) The Drosophila caspase Dredd is required to resist Gram-negative bacterial infection.
EMBO Reports 1:353-358.
Rodriguez A, Chen P, Oliver H, Abrams JM (2002) Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila
Apaf-1 homolog, Dark. EMBO Journal 21:2189-2197.
Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A (2004) Identification of mammalian microRNA host genes and transcription units. Genome Research
14:1902-1910.
Chew SK, Akdemir F, Chen P, Lu WJ, Mills K, Daish T, Kumar S, Rodriguez A, Abrams JM (2004) The apical caspase dronc governs programmed and unprogrammed cell
death in Drosophila. Developmental Cell 7:897-907.
Sang TK, Li C, Liu W, Rodriguez A, Abrams JM, Zipursky SL, Jackson GR (2005) Inactivation of Drosophila Apaf-1 related killer suppresses formation of
polyglutamine aggregates and blocks polyglutamine pathogenesis. Human Molecular Genetics 14:357-372.
Akdemir F, Farkas R, Chen P, Juhasz G, Medved'ová L, Sass M, Wang L, Wang X, Chittaranjan S, Gorski SM, Rodriguez A, Abrams JM (2006) Autophagy occurs
upstream or parallel to the apoptosome during histolytic cell death. Development 133:1457-1465.
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M,
Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608-611.
Vigorito E, Perks KL, Abreu-Goodger C, Bunting S, Xiang Z, Kohlhaas S, Das PP, Miska EA, Rodriguez A, Bradley A, Smith KG, Rada C, Enright AJ, Toellner KM,
Maclennan IC, Turner M (2007) microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27:847-859.
Contact Information
- Antony Rodriguez, Ph.D.
- Department of Human and Molecular Genetics
- Baylor College of Medicine
- One Baylor Plaza, ABBR806
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-1980
- Fax:
- E-mail: antonyr@bcm.edu
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