Transcript No Slide Title

Epigenesis
and
Genetic Regulation
Mechanisms of Gene Expression
1) X chromosome inactivation (Lyonization)
2) Genomic Imprinting
3) RNA Splicing
4) Photocopy (Transcriptional) Regulation
4.a) Methylation
4.b) Transcription Factors
5) Packaging (Post-Translational) Regulation
X Chromosome Inactivation
(Lyonization)
•At fertilization, both X chromosomes are active.
•Very soon, however, one of the X chromosomes in a cell,
apparently taken at random, is inactivated and forms a Barr
body.
•All other cells derived from the initial cell have the SAME X
chromosome inactivated.
•Genes on the inactive X chromosome are not expressed.
•In humans, though, a few genes are expressed.
Barr Bodies
Mechanism
•XIST gene on the X chromosome turns on
and produces XIST RNA.
•Molecules of XIST RNA accumulate along
the chromosome with the active XIST gene.
•The binding of the XIST RNA with the DNA
turns off the genes on that chromosome.
XX
X
X
X
X
Black
Fur
X
X
Orange
Fur
RNA Splicing
RNA transcript before editing:
exon 1
intron 1
exon 1
exon 2
exon 2
exon 3
mRNA after editing:
Polypeptide 1
intron 2
exon 4
exon 3
intron 3
exon 1
exon 4
exon 2
intron 4
exon 3
mRNA after editing:
Polypeptide 2
exon 5
exon 5
snRNP (snurps) =
small nuclear ribonucleoprotein particles
RNA Splicing
• Varies among species.
• Possible reason why number of human
genes is so small.
• Example = Amyloid Precursor Protein
(APP) gene.
• Might be very common in the human
brain.
Genomic Imprinting
• Some genes are turned off when inherited
from the father and turned on when inherited
from the mother.
• Other genes are turned on when inherited
from father but turned off when inherited from
mother.
• Mechanisms: methylation; phosphorylation of
histones.
Transcriptional Regulation:
I: Methylation
• Methyl group (CH3) added to DNA
• Shuts off genes (prevents transcription)
• Tissue specific (e.g., genes methylated in the
MHC differ in different tissues)
•Human Epigenome Project (map the
methylated DNA areas in the human genome)
Transcriptional Regulation:
II: Transcription Factors
Transcription factor (regulatory protein)
= protein or protein complex that
enhances or inhibits transcription.
Regulatory Protein
DNA
Transcription Stuff
E. Coli Cell
Regulatory Protein
DNA
mRNA
Transcription
Stuff
lactose
(a) LAC Operon Turned Off
(b) LAC Operon Turned On
Regulatory Protein
Regulatory Protein
DNA
mRNA
Transcription Stuff
E. Coli Cell
DNA
Transcription
Stuff
lactose
CRH
(Hypothalamus)
ACTH
(Pituitary)
-
+
Cortisol
(Adrenal)
Rolling winds send a tree trunk and
debris your way. Thankfully, your stress
system helps you cope. The brain's
hypothalamus releases the hormone
corticotrophin-releasing factor (CRF) and
its effects make your guard go up. CRF
travels to the pituitary gland and triggers
the release of adrenocorticotropic
hormone (ACTH). This hormone travels
in the blood to the adrenal glands and
instructs them to release a third
hormone, cortisol. The hormones rally
the body systems and provide energy to
help you deal with the stressful situation.
You quickly flee. Perpetual or severe
stress, however, may upset the stress
system and harm the brain.
http://web.sfn.org/content/Publications/BrainBriefings/stress.html
http://www.amtamassage.org/journal/su_00_journal/images/body2.jpg
CREB:
Transcription factor in neurons
CREB
(cyclic AMP Response Element Binding Protein)
Spermatogenesis
CA
cAMP
Circadian
rhythms
Protein
kinases
Long-term
memory
Phosphorylation
Posttranslational Modification:
Protein Activation/Deactivation
• Phosphorylation (add a phoshate group)
• Acetylation (add an acetyl group)
• Alkylation (add a ethyl, methyl group)
• Ubiquitination (add the protein ubiquitin
to an existing protein usually instructs the
cellular machinery to degrade/destroy the
protein)
Epigenesis and
Development
Homeobox Genes
Homeobox & Hox Genes
(Drosophila and Mus)
http://www.people.virginia.edu/~rjh9u/homeo.html
Homeobox & Hox Genes
(Drossophila, Mus & Homo)
http://universe-review.ca/F10-multicell.htm
Development
(Drosophila and Homo)
http://universe-review.ca/F10-multicell.htm
Hox Genes, which control the
development of the central nervous
system and the body, are common to
most organisms. Four groups of similar
Hox Genes, shown in color, appear to
control related regions of the human body
and the fly. Each box represents a single
Hox Gene.
http://web.sfn.org/content/Publications/BrainBriefings/hox_genes.html
Mammalian Sexual Development
1) Typical Course = Female
2) Males = “Masculinized” Females
2.a) 7th week: SRY gene
2.b) testes development
2.c) large amounts of androgens  masculinization
http://www.ncbi.nlm.nih.gov/disease/SRY.html
Examples of genetic
regulation and
epigenesis
Neurotrophic Factors:
A family of proteins produced in
various tissues that guide the growth,
migration, development and survival of
neurons and repair the processes (e.g.,
dendrites) of damaged neurons
A neuron or support cell (e.g., the
astrocyte) releases the neurotrophic
factor which binds to a receptor. The
binding initiates a signal that regulates
gene transcription. The protein products
then influence the growth, etc. of the
neuron. It may, for example, cause a
process of the neuron to grow in the
direction of the signal.
http://web.sfn.org/content/Publications/BrainBriefings/
neurotrophic.html#fullsize
Axons locate their target tissues by using
chemical attractants (blue) and repellants
(orange) located around or on the surface
of guide cells. Left: An axon begins to
grow toward target tissue. Guide cells 1
and 3 secrete attractants that cause the
axon to grow toward them, while guide
cell 2 secretes a repellant. Surfaces of
guide cells and target tissues also display
attractant molecules (blue) and repellant
molecules (orange). Right: A day later, the
axon has grown around only guide cells 1
and 3.
As the brain develops, neurons
migrate from the inner surface to
form the outer layers. Left:
Immature neurons use fibers from
cells called glia as highways to
carry them to their destinations.
Right: A single neuron, shown
about 2,500 times its actual size,
moves on a glial fiber.
http://web.sfn.org/content/Publications/
BrainBriefings/neuron.html
Experience influences the brain
If bigger brain parts mean a
bigger intellect, musicians may
have a leg up on others. Brain
imaging research shows that
several brain areas are larger in
adult musicians than in
nonmusicians. For example, the
primary motor cortex and the
cerebellum, which are involved in
movement and coordination, are
bigger in adult musicians than in
people who don't play musical
instruments. The area that
connects the two sides of the
brain, the corpus callosum, is also
larger in adult musicians.
http://web.sfn.org/content/Publications/BrainBriefings/music_training_and_brain.htm
Chronic administration of morphine
in rats shrinks dopamine neurons in
the reward circuit. The receiving
branches, called dendrites, wither
and the filaments that transport
important substances down the
neuron's axon are reduced. Nerve
growth factors appear to reverse the
damage.
http://web.sfn.org/content/Publications/BrainBriefings/addiction.html
In the brain, certain cells can release
glutamate. This chemical can then
activate molecular complexes, including
the AMPA receptor and NMDA receptor,
on nearby brain cells and create
reactions that aid memory, according to
studies. Another molecule, the GABA B
receptor, appears to suppress the
process. A number of researchers are
developing and testing compounds that
target components of this system in an
effort to create medicines that can
enhance memory and thinking.
http://web.sfn.org/content/Publications/BrainBriefings/mem_enhance.html
Comparative Genomics
•Tracing similarities/differences in human genes
and genes of other mammals.
•Nascent discipline because genome of our closest
relative (chimp) sequenced in 9/2005.
•Preliminary results suggest that a number of
differences may be due to genes coding for
transcription factors.
•E.g., FOXP2 may influence language