Basic silencing model II
M a c in to s h P IC T im a g e fo rm a t
is n o t s u p p o rte d
•Simple to analyze this in steady-state •Critical parameter q - how much miRna is degraded per degraded mRNA (in processed state)
Effective silencing requires
that s > Q m+, where =ms/.
Sharp silencing threshold
Threshold Effect
Cartoon
vs
Reality
•RyhB miRNA regulation of sodB •Threshold-linear units, similar to some neuron models •Also, fluctuations reduced in silenced state •From E. Levine, T. Hwa lab
M a c in to s h P IC T im a g e fo r m a t
is n o t s u p p o r te d
Local vs. Global parameters
Complex interplay of local and global parameters
• Different protocols can give opposite answers if these are not carefully controlled
Voinnet (2005)
Effective equations:
M a c in to s h P IC T im a g e fo r m a t
is n o t s u p p o r te d
with
M a c in to s h P IC T im a g e fo r m a t
is n model, the repression ratio can be altered by cell state (global) variables such as the transport into and out of the processed state, and miRNA loss (q)
RISC = RNA-induced Silencing Complex
MicroRNA formation
miRNA’s are processed from several precursor stages
Mammalian genomes seem to have 100’s of miRNA’s
Post-trancriptional Regulation by microRNA’s
Herbert Levine Center for Theoretical Biological Physics, UCSD
with: E. Levine, P. Mchale, and E. Ben Jacob (Tel-Aviv)
Local vs. Global parameters
Global control through the effective parameter
M a c in to s h P IC T im a g e fo r m a t
is n o t s u p p o r te d
Gives different repression ratios for same system of miRNA and target, different cellular context
• q=0 miRNA is completely recycled (catalytic mode) • q>0 miRNA is partially degraded (stoichiometeric) • q<0 amplification (occurs for siRNA)
Results
Local vs. Global parameters
• Data on silencing has been very controversial, with disagreements as to whether there is both mRNA and protein repression or only protein repression
– Motivation: Complementary expression patterns
• And, the miRNA might diffuse from cell to cell
– Motivation - intercellular transport of siRNA in plants – Could this be an actively maintained front with q<0?
– Simple physics but complex biology
Spatial sharpening
• What happens if we have a miRNA expressed with the opposite spatial pattern from its target mRNA?
Outline:
Introduction Basic model Spatial sharpening Temporal Sequencing
What are MicroRNA’s?
• MicroRNA’s (miRNA’s) are small noncoding RNA molecules that regulate eukaryotic gene expression at the translation level