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Transcript 
microRNA
Cass Jabara
Exam Questions
 What are microRNAs, and what is their
primary function?
 Where are microRNAs commonly found
in the human genome, and how does
this correlate to disease?
Background
miRNA - miR - microRNA
 Eukaryotes
 S.S. RNA
 19- to 25-nt
 Non-coding
Regulates gene expression
 Evolutionary conserved
≠ mRNA!
Eukaryotic Genome
1/3 of genes
regulated
Processing
DNA
RISC
transcription
pri-miRNA
mature
miRNA
Drosha processing
Dicer processing
pre-miRNA
Exportin 5-induced export
NUCLEUS
CYTOPLASM
miRNA Function
5’
3’
5’
AAAAAAAAAAA
Translation
3’
mRNA
miRNA Functions
 Cellular division - coordination
 Developmental apoptosis
 Stress resistance
 Fat metabolism
 Positive or negative regulation
Primary Literature
Novel miRNA ID
 Bioinformatics
Scan for conserved hairpin structure
Conserved, repetitive, protein coding
Thermodynamic stability
Expression of predicted miRNAs - microarrays
Validate microarray hits via cloning and
sequencing, fish via capture biotinylated
oligonucleotides
 Placenta, testis, thymus, brain, prostate
Oligonucleotide Capture
Bentwich et. al, 2005
miRNA Clusters
 Cluster 1 - Chromosome 19 - placenta only
 54 miRNAs - largest cluster discovered
 Expression parallels human embryonic stem cells
 Conserved in primates only
 Cluster 2 - X Chromosome - testis only
 10 miRNAs
 10 conserved in primates only
 7 conserved in dog
 4 conserved in mouse and rat
Significance
 Human miRNA total >800
 (vs current knowledge of 222)
 Conserved only 400-500
 Significant miRNA evolution unique to
primates
 89 Novel miRNAs discovered
 53 not conserved under primates
 Primate-specific developmental expression
indicates important role in mammalian
complexity
miRNA and Cancer
 Novel tumorigenesis gene class
e.g. 13q14 deletions - miR-15a, miR-16a
B cell chronic lymphocytic leukemia
Mantle cell lymphoma
Multiple myeloma
Prostate cancer
miRNA Locations
 HPV Integration Sites
oncogenes
 FRAs - Fragile Sites
 Loci prone to metaphase breakage
 Rearrangement or deletions in cancer
 CAGR - Cancer-associated genomic regions
 LOH - loss of heterozygosity (e.g. p53, RB)
 HOX - homeobox clusters
 Developmental gene regulation
Calin et. al, 2003
Summary
 microRNAs - 19-25nt - regulates gene
expression
 Over 800 predicted, many primate
conserved, may play role in complexity
 Positive and negative regulation, novel
tumorigenesis gene class
References
 Bentwich, I., Avniel, A., Karov, Y., Aharonov, R., Gilad, S., Barad, O.,
Barzilai, A., Einat, P., Einav., E., Meiri., E., Sharon, E., Spector, Y.,
Bentwich, Z. (2005) Identification of hundreds of conserved and
nonconserved human microRNAs. Nature 7: 766-770.
 Calin, G.A., Sevignani, C, Dumitru, C.D., Hyslop, T., Noch, E.,
Yendamuri, S., Shimizu, M., Rattan, S., Bullrich, H., Negrini, M., Croce,
C.M. (2003) Human microRNA genes are frequently located at fragile
sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci.
101: 2999-3004
 “microRNA (miRNA) Resource” Ambion.
http://www.ambion.com/techlib/resources/miRNA/index.html
 “MicroRNA” Wikipedia. http://en.wikipedia.org/wiki/MicroRNA
 “RNA-induced Silencing Complex” Wikipedia.
http://en.wikipedia.org/wiki/RNA-induced_silencing_complex
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