Download notes

UEBiophysics
Regula'onofgeneexpression
DanielJost
CNRS,LaboratoireTIMC-IMAG,Grenoble
Contact:[email protected]
Web:hOp://membres-Qmc.imag.fr/Daniel.Jost/
MasterdegreeinPhysics2016/2017–ENSLyon
Modelinggeneexpression
v  Aims:explainthephysicalandmathema7calbasisofmodelscurrentlyusedinsystems
biologytomodelGNR
Ø  Modelingthecentraldogmaofmolecularbiology
1)DeterminisQcmodeling
2)StochasQcmodeling
Ø  Beyondthecentraldogma:
1)interacQonbetweengenes
2)MoQfanalysis
3)Networkinference
Modelingthecentraldogma:stochas'capproach
v  RecalldeterminisiQcpart:«InallthissecQon,wewillassumethatthenumberof
involvedmoleculesishigh(withweakfluctuaQons),sowecanmodelmRNAor
proteinnumbersasconQnuousvariablesrepresenQngtheaveragevalueswithinthe
cellpopulaQon.»
v  Geneexpressionisintrinsicallystochas7c/probabilis7c
ExpressionofareportergeneexpressedinE.coli
Modelingthecentraldogma:stochas'capproach
v  Geneexpressionisintrinsicallystochas7c/probabilis7c
Ø  Intrinsicvariability:biochemicalreacQonsareintrinsicallystochasQcandmay
involveasmallnumberofelements.Thenumbersofmoleculesinacellarediscrete
andtheyfluctuateinQme,evenundersteady-statecondiQons.
Tyagi,2015
factorX
promoterregion gene
Bionumbers.org
Ø  Extrinsicvariability:fluctuaQonsduetoenvironment/intra-cellularheterogeneiQes
Modelingthecentraldogma:stochas'capproach
v  Stochas7cmodelsaimtodescribesuchdiscretenessandnoise.
v  Twomainapproaches:
Ø  Computeprobabilitydistribu7onsasafuncQonofQme
Ø  Computepossibletrajectoriesofthebiochemicalsystem
Modelingthecentraldogma:stochas'capproach
v  mRNAproduc7on:weaimtodescribetheprobabilityP(m,t)ofhavingmmRNAin
acellatQmet.
Ø
α
mRNA(m)
β
Ø
Modelingthecentraldogma:stochas'capproach
v  Stochas7csimula7on:theGillespiealgorithm:simulaQngexactstochasQctrajectories
m(t)
m(t)
+1
-1
+1
-1
t1
t2 t3
Qme
t1
+1
+1
t2
t3
Qme
Ø  Fromthe(many)trajectories:esQmatePorcomputeaverage,noise,etc.
Whenwillthenextreac7onoccur?
Whatisthereac7on?
Modelingthecentraldogma:stochas'capproach
TD3:extrinsicnoiseandmodelforproteins
Modelingthecentraldogma:stochas'capproach
v  Transcrip7onbursts:Inregulatedpromoters,transcripQonmaybealsobursty.Promoter
statealternatebetweenanONandOFFstate,leadingtoenhancednoiseiftheswitching
rateislow.
Kimetal,2013
factorX
promoterregion gene