Epigenesis and Genetic Regulation

Epigenesisand

Genetic Regulation

Mechanisms of Gene Expression

1) X chromosome inactivation (Lyonization)

3) RNA Splicing

4) Photocopy (Transcriptional) Regulation

5) Packaging (Post-Translational) Regulation

2) Genomic Imprinting

4.a) Methylation

4.b) Transcription Factors

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.

X

XX

BlackFur

X

X X

OrangeFur

X X

exon 1 intron 1 exon 2 exon 5exon 4exon 3 intron 3intron 2 intron 4RNA transcript before editing:

exon 1 exon 2 exon 4exon 3 exon 1 exon 2 exon 3 exon 5

mRNA after editing: mRNA after editing:

RNA Splicing

Polypeptide 1 Polypeptide 2

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

Transcription Stuff

DNA

E. Coli Cell

DNA

mRNA

lactose

Regulatory Protein

TranscriptionStuff

Regulatory Protein

Transcription Stuff

DNA

E. Coli Cell

DNA

mRNA

lactose

Regulatory Protein

TranscriptionStuff

(a) LAC Operon Turned Off (b) LAC Operon Turned On

CRH

ACTH

Cortisol

+-

(Pituitary)

(Hypothalamus)

(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

CA cAMPProtein kinases

Phosphorylation

CREB(cyclic AMP Response Element Binding Protein)

Spermato-genesis

Circadian rhythms

Long-term memory

CREB:Transcription factor in neurons

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

http://www.people.virginia.edu/~rjh9u/homeo.html

Homeobox & Hox Genes(Drosophila and Mus)

http://universe-review.ca/F10-multicell.htm

Homeobox & Hox Genes(Drossophila, Mus & Homo)

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 invarious 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

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

Experience influences the brain

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