Mechanisms

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BE700 / BF600
Mechanisms Models of Cellular Regulation
Baltazar D. Aguda, PhD
bdaguda_at_bu.edu Dept Genetics Genomics,
BU Sch of Med Tel. (617) 414
1654 Dept Biomedical Engineering, BU Coll Eng
http//biopathways.bu.edu/BE700
Course outline schedule Recommended readings
references Lecture powerpoint slides Web
links Problem Sets, Projects Comments
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Course Overview
WEEKS
TOPICS

1 Basic cell
biology Levels of cellular regulation
2 Gene structure
transcription control elements
3 Gene regulatory
networks (GRNs)
4-6 Mathematical
modeling and computer simulation of GRNs
7-8 Engineering
control of GRNs
9 Metabolic
networks
10 Signal
transduction pathways
11 Cell division and
death (apoptosis)
12 Platforms of
Systems Biology
13 Pathway inference
pathways databases
14 Biotechnology
trends Project Presentations
15 Course summary (1
lecture)
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After taking this course, you would have learned
.
how to think as a dynamicist (translate
mechanisms into kinetic models)
how to solve and analyze the mathematical models
to appreciate the necessity of an integrative
approach to understanding cellular regulation
(systems biology)
the possible means of extracting models from
-omic data
some interesting open research problems
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Teaching/Learning Methods
Lectures on the basics assigned readings
Discussion of 1 or 2 research articles/case
studies per week (discussion leaders
assigned class participation required) or
guest lecturers
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FIRST WEEK
Basic Cell Biology
The Cell its Achitecture
Levels of regulation
Cellular/Biological Processes
Physico-Chemical Processes
First focus
Gene Expression
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The Cell its Achitecture
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From Lodish et al., Fig 1-5.
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E. Coli bacteria has about 1,500 ribosomes
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Animal cell
http//sun.menloschool.org/birchler/cells/
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Ribosomes in prokaryotes and eukaryotes
Fig 4-32 of Lodish et al.
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PHOSPHATES
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This organelle can be described as the
processing and distribution center of the cell
factory where proteins received from the E.R.
are again processed and passed on to the
lysosomes or plasma membrane or secreted.
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Plasma Membrane
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Cellular/Biological Processes
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Biological phenomena
Reproduction growth and division
mitosis
meiosis Differentiation stem cells to
specialized cells Death apoptosis
(programmed), necrosis Developmental program
(multicellular organisms)
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MITOSIS
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MEIOSIS
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UNICELLULAR TO MULTICELLULAR
Life cycle of a cellular slime mold,
Dictyostelium discoideum http//www.rinshoken.or.j
p/org/EM/sem-p1-e.htm
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DEVELOPMENT
(Cell Differentiation)
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PROGRAMMED CELL DEATH (apoptosis)
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See movie on cell cycle and other cellular
processes
http//www.ncbi.nlm.nih.gov/books/bv.fcgi?callbv.
View..ShowSectionridmcb.figgrp.215
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Physico-Chemical Processes
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Universality in biochemical composition of
terrestial life forms and similar principles of
organization at the cellular level.
Building blocks
nucleic acids (RNA, DNA) proteins carbohydrates li
pids, etc.
Energetics, Synthesis Degradation of
Biomolecules
metabolism gene expression
Transmission of hereditary information
gene expression epigenetics
Responding to environment
molecular signal transduction mechano-chemical
signaling
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Single-strand DNA
5 3 directionality
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DNA double helix
From book of Lodish et al.
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RNA secondary tertiary structures
From book of Lodish et al.
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Proteins
amino acids
human insulin
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Carbohydrates
polysaccharides
disaccharides
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Lipids
micelle
bilayer membrane
phospholipids
fatty acids
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http//www.genome.ad.jp/kegg/pathway.html
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Synthesis of Biopolymers
Proteins and nucleic acids from a small number of
monomers 5 nitrogenous bases in nucleic
acids 20 amino acids in
proteins
Monomers added one at a time
Specific starting point, growth proceeds in one
direction to a fixed terminus amino- to carboxyl
terminus in proteins 5 to 3 end in nucleic
acids
Primary synthetic product often modified
Covalent modifications methylation,
phosphorylation, acetylation, etc.
from Lodish et al..
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Supramolecular organization of biomolecules
A
T
C
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Gene Expression
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CENTRAL DOGMA
DNA
TRANSCRIPTION
RNA mRNA tRNA rRNA
TRANSLATION
PROTEINS
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3 Roles of RNA in protein synthesis
Fig 4-20 of Lodish et al.
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CENTRAL DOGMA
DNA
TRANSCRIPTION
RNA mRNA tRNA rRNA
TRANSLATION
PROTEINS
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Transcription Steps
From book of Lodish et al.
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Overview of RNA processing in eukaryotes
(example ?-globin gene)
Watch movie Life cycle of an mRNA clickable at
bottom of Fig 4-19 caption in online textbook of
Lodish et al. (Section 4.3).
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Structure of the 5 methylated cap of eukaryotic
mRNA (Fig 4-18, Lodish et al.)
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THE GENETIC CODE
(RNA to amino acid)
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Translation of nucleic acid sequences in mRNA
into amino acid sequences in proteins requires a
two-step decoding process. Fig 4-25 of Lodish et
al.
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Structure of tRNAs
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a digression on the term projects coming up...
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Term Projects
Suggested Topics 1. initiation of DNA
transcription 2. initiation of DNA
replication 3. cell cycle control in budding
yeast (S. cerevisiae) 4. cell cycle control in
the bacterium E. coli 5. initiation of
apoptosis 6. replication kinetics of a
retrovirus 7. regulation of the Ras-MAP kinase
signal transduction pathway 8. regulation of
E2F-1 expression and transcriptional activity 9.
intracellular signaling pathways inducing c-myc
expression 10. dynamic Bayesian networks and
time-series gene expression data on the
human cell cycle 11. energetics of the cell
cycle (coupling with metabolic pathways) 12.
mitotic checkpoint (chromosome segregation) 13.
DNA damage checkpoints 14. on non-coding RNAs
I have lead articles for most of the topics
above. You can also suggest your own topic.
Work in pairs or individually.
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web homepage design
Title of project here
Name of investigators here
Define limits of the project
Home
Specific Aims
Biological molecular info from the literature
Mechanisms
Model Development
Model Analysis
Essential players interactions, rates
References
Mathl analysis computer simulations, discussion
Useful Links
Contact us
List refs. include links pdfs if available
Existing websites on the topic
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Term project milestones/deadlines
grading
Week
form groups, select topic
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3
website/knowledgebase created
5/40
model mechanism ready for analysis
10/40
7
12
model analysis progress report due
10/40
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class presentation of project final website
15/40
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Steps in creating your website/knowledgebase
1. Download YahooSiteBuilder from
http//webhosting.yahoo.com/ps/sb/
2. Go through tutorial and start building your
site in your PC.
3. Ask Mr. Yuan Cheng (in the Aguda Lab, Room
108) to create an account for you in our
server (biopathways.bu.edu). Mr. Chengs
email address is ycheng_at_bu.edu
4. Upload your website into your account in our
server. Email Mr. Cheng for instructions.
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back to the lectures .
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Fig 4-27 of Lodish et al.
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A coarse-grained/general gene expression
regulatory network model (will be updated as
we progress in the course)
modif. proteins
rRNA
tRNA
mRNA
proteins
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post-translational modifications
modif. proteins
rRNA
tRNA
mRNA
DNA
1o RNA
proteins
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hot topic junk DNA, non-coding RNAs,
transcriptional units
modif. proteins
rRNA
tRNA
mRNA
DNA
proteins
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The Aguda Lab (primarily the work of Yuan Cheng)
has a knowledgebase for non-coding RNAs
http//biopathways.bu.edu/ncRNA
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RNA interference
(RNAi)
Fig C.9 of Hartwell et al. Genetics From genes
to genomes McGraw Hill. C2004.
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RNAi
modif. proteins
rRNA
tRNA
mRNA
DNA
1o RNA
proteins
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encoding qualitative information into a dynamical
model expression of a protein
with n amino acids
(this is just to give you a taste of whats to
come...)
amino acids
DNA
tRNA
4
primtRNA
m 1,..n
1
7
2
5
primrRNA
rRNA
3
6
primmRNA
mRNA
protein
example of a protein inducing its own expression
If the tRNAs and rRNAs are at steady state
dprotein/dt v7(mRNA,aminoacids) -
vpdeg(protein) dmRNA/dt v6(primmRNA)
- vmdeg(mRNA) dprimmRNA/dt v3(protein) -
v6 (primmRNA) - vpmdeg(primmRNA)
We do not know the functional forms of the vs.
Also, what if the tRNAs and rRNAs are
variable? Well learn more how to model later.
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Readings on non-coding RNAs
Mattick JS. Challenging the dogma the hidden
layer of non-protein-coding RNAs in complex
organisms. Bioessays. 2003 Oct25(10)930-9.
pdf can be downloaded from http//biopathways.bu
.edu/ncRNA (click on Library)
Gibbs WW. The Unseen Genome Gems among the
Junk", Scientific American, Nov2003, pp.
47-53. pdf available from course website
http//biopathways.bu.edu/BE700
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Gibbs WW. The Unseen Genome Gems among the
Junk", Scientific American, Nov2003, pp. 47-53.
98 non-protein-coding lt2 protein-coding
1194 conserved sequences 244 of these within
protein-coding seqs 2/3 are in introns, rest in
intergenic seqs
Comparative genomics of 12 animal species
The hidden (epigenetic) layer of gene expression
regulation
pseudogenes
antisense RNA at least 1600 human genes make
antisense RNA
RNAi machinery (genome censor protection from
viruses)
microRNAs
RNA-only genes
riboswitches
NHGRI project called ENCODE (Encyclopedia of DNA
Elements)