Download Control of Gene Expression

Control of Gene Expression
Eukaryotes
Eukaryotic Gene Expression
• Some genes are expressed in all cells all the time.
These so-called housekeeping genes are
responsible for the routine metabolic functions
(e.g. respiration) common to all cells.
• Some are expressed as a cell enters a particular
pathway of differentiation.
• Some are expressed all the time in only those cells
that have differentiated in a particular way. For
example, a plasma cell expresses continuously the
gene for the antibody it synthesizes.
• Some are expressed only as conditions around
and in the cell change. For example, the arrival of
a hormone may turn on (or off) certain genes in
that cell
One Gene = One Protein Hypothesis
• By Beadle and Tatum (1940’s)
• The one gene-one enzyme
hypothesis is the idea that
genes act through the
production of enzymes, with
each gene responsible for
producing a single enzyme that
in turn affects a single step in a
metabolic pathway.
• http://www.dnalc.org/view/163
60-Animation-16-One-genemakes-one-protein-.html
The Eukaryotic Gene
• Associated with most eukaryotic genes are control elements, segments of
noncoding DNA that help regulate transcription by binding certain proteins
• Control elements and the proteins they bind are critical to the precise regulation
of gene expression in different cell types
Many Levels of Control in Eukaryotes
• Chromatin Remodeling The region of the
chromosome must be opened up in order for
enzymes and transcription factors to access the gene
• Transcription Control The most common type of
genetic regulation
• Turning on and off of mRNA formation
• Post-Transcriptional Control Regulation of the
processing of a pre-mRNA into a mature mRNA
• Translational Control Regulation of the rate of
Initiation
• Post-Tranlational Control (protein activity control)
Regulation of the modification of an immature or
inactive protein to form an active protein
Chromatin Remodeling
• Genes within highly packed
heterochromatin are usually
not expressed
• Chemical modifications to
histones and DNA of chromatin
influence both chromatin
structure and gene expression
• Requires ATP
Chromatin Remodeling
• In histone acetylation, acetyl groups
are attached to positively charged
lysines in histone tails, which
neutralizes them
• The addition of methyl groups
(methylation) can condense
chromatin; the addition of phosphate
groups (phosphorylation) next to a
methylated amino acid can loosen
chromatin
Chromatin Remodeling
Transcription Control
• To initiate transcription, eukaryotic RNA polymerase requires the
assistance of proteins called transcription factors
• In eukaryotes, high levels of transcription of particular genes depend
on control elements interacting with specific transcription factors
• Proximal control elements are located close to the promoter
• Distal control elements, groups of which are called enhancers, may be
far away from a gene or even located in an intron
• An activator is a protein that binds to an enhancer and stimulates
transcription of a gene
Transcriptional Control
Transcriptional Control
• Methylation of bases also turns off
transcription
• DNA methylation can cause long-term
inactivation of genes in cellular differentiation
• In genomic imprinting, methylation regulates
expression of either the maternal or paternal
alleles of certain genes at the start of
development
• Although the chromatin modifications just
discussed do not alter DNA sequence, they may
be passed to future generations of cells
• The inheritance of traits transmitted by
mechanisms not directly involving the
nucleotide sequence is called epigenetic
inheritance
Post-Transcriptional Control
• Alternative RNA splicing: different mRNA molecules are produced
from the same primary transcript, depending on which exons are
spliced out by the splicosome
• mRNA degradation: without a 5’ cap and poly-A tail an mRNA will be
destroyed
Post-Translational Control (protein activity)
• After translation, various types of protein processing, including cleavage and
the addition of chemical groups, are subject to control
• Proteasomes are giant protein complexes that bind protein molecules and
degrade them
• Ubiquitin's are placed on any protein as the signal for it to be degraded in the
proteasome
Noncoding RNAs
• Only a small fraction of DNA codes for
proteins, rRNA, and tRNA
• A significant amount of the genome
may be transcribed into noncoding
RNAs
• Noncoding RNAs regulate gene
expression at two points: mRNA
translation and chromatin configuration
MicroRNAs
• MicroRNAs (miRNAs) are small
single-stranded RNA molecules
that can bind to mRNA
• These can degrade mRNA or block
its translation (translational
control)
siRNAs
• The phenomenon of inhibition of gene
expression by RNA molecules is called RNA
interference (RNAi)
• RNAi is caused by small interfering RNAs
(siRNAs)
• siRNAs play a role in heterochromatin
formation and can block large regions of the
chromosome
• Small RNAs may also block transcription of
specific genes
miRNA vs. siRNA
• both are formed from dsRNA and both eventually get cleaved into
pieces by Dicer and then incorporated into RISC which in effect
cleaves target mRNA.
• siRNAs and miRNAs are similar but form from different RNA
precursors
• Sirna Therapeutics, Inc. was a San Francisco, California based
biotechnology company that explores the use of RNA interference in
human disease therapy. Sirna's development pipeline includes several
small interfering RNA (siRNA) drugs, thought to stably silence the
expression of specific disease-related genes.