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Marco Magistri
09-11-2007, Journal Club
A non-coding RNA (ncRNA) is any
RNA molecule that is not translated
into a protein
“Structural genes encode proteins and regulatory genes produce
non-coding RNAs”
1961, Jacob and Monod
21561 protein-coding genes
VS
69185 transcribed regions
Genome paradox: as an organism’s
complexity increases, the protein
coding contribution of its genome
decreases.
ncRNAs may contribute to the complex networks that regulate cell
function and could be the ultimate answer to the genome paradox
Housekeeping
ncRNAs
Regulatory
ncRNAs
Constitutively expressed and
required for normal function and
viability of the cell.
i.e.: transfer RNAs (tRNA),
ribosomal RNAs (rRNA), small
nuclear RNA (snRNAs), small
nucleolar RNAs (snoRNA), etc.
Expressed at certain stages of
development, during cell
differentiation, or as a response to
external stimuli, wich can affect
the expression of other genes at
the level of transcription or
translation.
i.e.: small interfering RNAs
(siRNA), microRNA, etc.
ncRNA are emerging as new and exciting players in gene
regulatory networks, and their deregulation may underlie
or be a marker for many complex diseases
Prasanth and Spector GENES & DEVELOPMENT 2007
Genomic Ultraconserved Region UCR
• The UCRs are a subset of absolutely conserved (100%) sequences
that are located in both intra- and intergenic regions
– Nonexonic: no evidence of encoding protein
– Exonic: overlapping mRNA of known function
– Possibly exonic
• The UCRs rapresent a small fraction of the human genome that
are likely to be functional but not encoding proteins and have been
called the ‘‘dark matter’’ of the human genome (Bejerano et al.,
2004).
Genome-wide Profiling Reveals Extensive
Transcription of UCRs in Normal Human
Tissues
Transcribed UCR (T-UCR) are expressed in normal tissue
both ubiquitously and in a tissue-specific manner
Expressed in
the minority
of tissues
Tissue
specifically
expressed
Expressed
in the
majority
of tissues
Ubiquitously
expressed
Hierarchical clustering of t-UCR
expression
UCRs represent noncoding
transcript with tissue-specific
level of expression
Distinct UCR signatures in human
leukemias and carcinomas
Specific groups of UCRs are differentially expressed in tumor types
Comparison of UCRs expression between normal
and tumor cell of the same origin
9.1% are differentially
expressed at a higly
statistically significant
level
Both upregulated and
downregulated in cancer
Signatures:
CLL: 19 UCRs (8up- and 11 downregulated)
CRC: 61 UCRs (59up- and 2 downregulated)
HCC: 8 UCRs (3up- and 5 downregulated)
T-UCR expression profiles can be used
to differentiate human cancer
UCRs are frequently located at fragile sites (FRA)
and cancer associated genomic regions (CAGR)
T-UCRs differentially expressed in human cancers
are located in CAGRs specifically associated with
that type of cancer
Negative regulation of T-UCR by
direct interaction with microRNA
Assays for miRNA:UCR interaction
Negative correlation between 87
miRNAs and T-UCRs expression
levels
T-UCRs as oncogenes
Conclusions
•
Some UCRs represent noncoding transcripts in human
normal tissues and their expression is tissue-specific
•
T-UCRs expression profiles can be used to differentiate
human cancers
•
UCRs are located in genomic regions altered during
malignant process, suggesting that T-UCR could be
candidate genes for cancer susceptibility
•
Noncoding T-UCR represent possible targets of miRNAs
and these interaction may have biological and prognostic
significance for cancer patients
•
In some cases T-UCRs behaves like oncogenes by increasing
the number of malignant cells as a consequence of reduced
apoptosis
• What is the key experiment?
(the one confirming the statement in
the title)
• What is the strongest point?
• What is the weakest point?
and What to do to strenghten it?
• What is the take home message?
(summarize it in a sentence)