Download THE ORGANIZATION AND CONTROL OF EUKARYOTIC GENOMES

REGULATION OF GENE
EXPRESSION
Chapter 18
Gene expression
• A gene that is expressed is “turned
on”.
• It is actively making a product
(protein or RNA).
• Gene expression is often regulated at
transcription.
• Newly discovered roles of RNA in
gene expression
Regulation of a metabolic pathway
Prokaryotic Gene Regulation
• Adjust activity of enzymes already
present
– Often through negative feedback
• Adjust production level of certain
enzymes
OPERONS
• Regulation in prokaryotes
– Operator – switch segment of DNA
in promoter
– Operon – the promoter, the
operator, and the genes they
control
– Regulatory gene – long distance
from gene that is regulated
The trp operon: regulated synthesis of repressible enzymes
trp animation
trp tutorial
The trp operon: regulated synthesis of repressible enzymes
The lac operon: regulated synthesis of inducible enzymes
lac operon animation
lac operon tutorial
The lac operon: regulated synthesis of inducible enzymes
• Regulatory gene makes protein
(repressor) that inhibits
operator
• Regulatory protein has inactive
and active shape
– Corepressor – makes
repressor active
– Inducer – inactivates repressor
• Repressible enzymes usually
used when cell makes something
(ex. tryptophan)
• Inducible enzymes usually used
when cell breaks something down
(ex. lactose)
Eukaryotic Gene Regulation
• Expression can be regulated at any
stage
• Differential gene expression –
different cells in an organism express
different genes from the genome
• Not all genes are turned on all of the
time!
Opportunities for the control of gene expression in eukaryotic cells
GENOME ORGANIZATION
• 1.5% of DNA in humans codes for
protein
• 24% introns and regulatory
• Most is repetitive DNA (59%)
• Unique noncoding is 15%
CHROMATIN
• Composed of DNA and proteins
called histones
• Nucloesome – DNA wrapped
around a histone
Levels of chromatin packing
Eukaryotic Regulation
• At DNA level
– Chromatin modification, DNA unpacking
with histone acetylation (turned on) and
DNA demethylation (turned off)
• At RNA level
– Transcription, RNA processing,
transport to cytoplasm
• At protein level
– Translation, protein processing,
transport to cellular destination, protein
degradation
• Regulation of transcription
– Transcription factors – mediate the
binding of RNA polymerase to the
promoter and other regulatory
proteins
– Enhancers – far upstream of gene;
bind to transcription factors; called
distal control element
Figure 19.8 A eukaryotic gene and its transcript
– Not many different control
elements so the combination of
control elements regulates gene
action
• Different combos of activators
(transcription factors) makes
different genes turn on
• Different genes can be turned on
by same activator
Cell-type specific transcription based on
available activators
DIFFERENTIAL GENE EXPRESSION =
DIFFERENT CELL TYPES
• Cell differentiation – process by which cells
become specialized in structure and function
• Morphogenesis – process that gives an organism its
form (shape)
• Pattern formation – development of spatial
organization in which tissues and organs are in their
correct places
• Positional information – molecular cues that
control pattern formation
• Homeotic genes – control pattern formation
CANCER
• Oncogenes- cancer causing genes
in retroviruses
• Proto-oncogenes – normal genes
that code for proteins that
stimulate cell growth and division
• Tumor suppressor genes - make
proteins that help prevent
uncontrolled cell growth
Converting proto-oncogene into oncogene
Converting proto-oncogene into oncogene
• Movement of DNA within a
chromosome
– May place a more active promoter
near a proto-oncogene (= more cell
division)
• Amplification of a proto-oncogene
• Point mutations in control element or
proto-oncogene (= more expression or
makes abnormal protein that doesn’t
get degraded or is more active)
GENES INVOLVED IN CANCER
• Ras gene – makes ras (G) protein that starts
cascade reactions that initiate cell division
– Mutations in Ras gene cause ~30% cancers
• p53 tumor suppressor gene – “guardian of
genome”
– Activates p21 which halts cell cycle
– Turns on genes to repair DNA
– Activates suicide proteins that cause cell death
(apoptosis)
– Mutations in P53 gene cause ~50% cancer
Multistep Model of Cancer Development
• Approximately half dozen changes have
to occur at the DNA level for cancer to
develop.
• Need at least one oncogene and loss of
tumor suppressor gene(s)
• Most oncogenes are dominant and most
tumor suppressor genes recessive so
must knock out both alleles
• Typically telomerase is activated
A multi-step model for the development of colorectal cancer
Inherited Predisposition to Cancer
• 15% colorectal cancers are inherited
– Most from mutated APC gene
(tumor suppressor gene)
• 5-10% breast cancers are inherited
– Most with mutated BRCA1 and
BRCA2
– A woman with one mutant BRCA1
gene (tumor suppressor gene) has a
60% chance of getting breast
cancer by age 50