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Introduction to Systems Biology. Craig Simpson. What is a system?. A collection of components organized to accomplish a specific function of set of functions A group of interacting, interrelated, or interdependent elements or parts that function together as a whole to accomplish a goal. - PowerPoint PPT Presentation
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Introduction to Systems Biology
Craig Simpson
What is a system?
1. A collection of components organized to accomplish a specific function of set of functions
2. A group of interacting, interrelated, or interdependent elements or parts that function together as a whole to accomplish a goal
Matthias Heinemann, ETH
What cellular processes are controlled by systems?
• Cell division (mitosis, meiosis)• Cell death (apoptosis,
autophagy, necrosis)• Cell differentiation• Cell movement• Metabolism• Catabolism/anabolism• i.e. every cellular process can
be considered a system or a network
How does information flow in a cell?
Highly simplified!!!
DNA ProteinRNA Function
From DNA to RNA
• Transcription takes place in the nucleus
• RNA is produced from DNA by RNA polymerase– RNA is produced from 1 strand of
DNA– Requires transcription factors
upstream of transcription start site
– Not all genes are transcribed equally
Transcritional regulation
• Promoter region– How accessible is it?
• DNA is tightly coiled• Promoter regions can be modified to shut down transcription
(epigenetic regulation)
• Activators– Enhance interaction between RNA polymerase and
promoter region• Repressors– Bind to regions close to promoter region and prevent RNA
polymerase from binding
RNA processing
RNA to Protein
• Translation takes place on the ribosomes
• Ribosomes read three nucleotide sequences (Codon) from mRNA and add corresponding amino acid to growing peptide chain– Use of tRNA
Codons are the code for which amino acid to use
Regulation of Translation
• mRNA availability• Presence of silencer/inhibitory RNA that binds
to mRNA• Codon usage (abundance of tRNA)• Amino Acids– 20 essential amino Acids
Shape and Structure of Protein
• Chemical bond between two amino acids (peptide bond)
• Composed of multiple peptide bonds between a composition of different amino acids– Chemical properties of the amino acids impart 3D
structure to the protein• Multiple peptides can bind together to form a
complete functional protein
Protein function• Protein’s structure determine its function• All proteins bind to some other molecule
– Tight and long lived interaction– Short and highly energetic reaction– Depends on the amino acid side chains
Metabolites
• End product of protein activity– Anabolic processes– Catabolic processes
• Depends on the context that the cell is in• Everything that is produced in a cell is a
metabolite– Metabolites can be measured
Posttranslational Modifications
• After protein is formed it is chemically modified on the amino acid side chains– Ubiquitylation, sumolation, on lysine– Phosphorylation on tyr, ser, thr– Acetelyation
• Modifications can alter the function of the protein– Mark for destruction– Activate– Change binding partners
Genetics do not dictate function
Function
DNAProtein
RNA
DNA
Protein
RNA
DNA
Protein
RNA
DNA
Protein
RNA
Cellular Process
• Cellular functions and processes are an accumulation of multiple different pathways and signals converging into one complex end point
• Need to understand these processes at a systems level to truly understand the process– Ie need to measure genetic mutations, presence
and levels of mRNA and expression and activity of proteins
Tools we can use to study the cellular system
• Mass Spectrometry– Total protein levels and post translational modificiations– metabolomics
• Sequencing– Genomic and exosome sequence
• Mutations in DNA, RNA
• Arrays– Levels of RNA
• Gene manipulation studies– Knockdown RNA– Overexpress RNA
• IE: Generate a large amount of data
Large amount of Data is meaningless
• Mass Spec: can generate 20-50,000 data points– Absence of protein doesn’t mean its not there
• Sequencing: 22,000 genes– Is a mutation functionally relevant?
• RNA expression: number depends on state of cell– Does a low expression level relate to decreased activity of
protein?• Metabolites: All the small molecules that the cell is
producing– Depends on state and type of cell
What does it all boil down to?
• Biology is governed by chemistry and physics• Chemistry and physics can be mathematically
modeled• Thus… biology can be mathematically
modeled
=
System biology work flowDNA MetabolitesProteinRNA
Modeling of all information (determine regulators of certain function)
Computer driven hypothesis of molecular regulators of function
DNA MetabolitesProteinRNA
Experimental manipulation
Where is system biology relevant?• Disease biology– Cancer– Infections– Diabetes– Any disease is caused by a perturbation to the normal cellular
system• Drug development– Understanding the system behind a disease will allow for
better targeting of disease– Understanding how drugs alter systems
• Many more…