Epigenesis Synonyms Gene Expression Gene Regulation Definition Anything
- Slides: 52
Epigenesis: Synonyms: Gene Expression, Gene Regulation Definition: Anything genetic above and beyond the sequence of nucleotides Importance: Everything, especially development and genetic responses to the environment.
Examples of Epigenesis: 1) Development: tissue differentiation and timing 1. A) Sex differentiation & behavior 1. B) Chimps versus humans 2) Response to internal and external environment: 2. A) Learning and Memory 2. B) Hormones: Stress and Dominance
Classification of Epigenesis I) Epigenetic Transmission II) Whole Chromosome Regulation (X chromosome inactivation or Lyonization) III) Regulation during Protein Synthesis III. A) Photocopy (Transcriptional) Regulation III. A. 1) Methylation III. A. 2) Histone Modification III. A. 3) Transcription Factors III. B) “Editing” Regulation 3. B. 1) Alternative RNA splicing III. C) Pre-translational Regulation 3. C. 1) “interfering” RNA IV) Regulation after Protein Synthesis IV. A) Many mechanisms
I) Epigenetic Transmission Two types of genetic transmission: 1) Blueprint transmission (sequence transmission) Transmission of information via the order of the nucleotides (A, C, G, T) 2) Regulatory transmission (epigenetic transmission) • Transmission of information about gene regulation • Transmission of genetics “above and beyond” the sequence of nucleotides
I) Epigenetic Transmission • Definitely occurs • Extent of its importance not known, especially for behavior. • No empirical evidence, one way or the other, for this in normal human behavior. • Mechanisms: methylation, histone modification
I) Epigenetic Transmission http: //discovermagazine. com/2006/nov/cover
I) Epigenetic Transmission • Behavioral Example: Denenberg & Rosenberg (1967) (simplified) • Grandmother rats either handled or not handled at an early age. • Grandchildren of handled grandmothers were more active (less anxious) than those of non-handled rats.
I) Epigenetic Transmission: Genomic Imprinting: Specific example of epigenetic transmission • Definition: The expression (active vs inactive) of a gene depends on which parent transmits the gene. • 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. • No confirmed examples for normal human behavior.
II) Whole Chromosome Regulation: X Chromosome Inactivation or 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. • Majority of genes on the inactive X chromosome are not expressed.
II) Lyonization Barr Bodies = inactivated X chromosome
II) Lyonization 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.
II) Lyonization XX X X Black Fur X X Orange Fur
III) Regulation during protein synthesis The following slides all illustrate genetic regulatory mechanisms at various stages of protein synthesis.
III. A) Transcriptional Regulation: 1. DNA Methylation 2. Histone Modification 3. Transcription Factors
III. A) Transcriptional Regulation: III. A. 1) DNA Methylation • Methyl group (CH 3) added to DNA • Dimmer switch turned down: Reduces/prevents transcription • Tissue specific (e. g. , genes methylated in the MHC differ in different tissues) • Very important in embryogenesis & tissue differentiation - zygote becomes unmethylated - series of methylations leads to tissue differentiation • Possible source of epigenetic transmission • Human Epigenome Project (map the methylated DNA areas in the human genome = “methylome”)
III. A) Transcriptional Regulation: III. A. 1) DNA Methylation No methylation: Transcription “stuff” can bind to a promoter C G C G T A T T A G T A C A A G M Methylated: Prevents transcription “stuff” from binding to a promoter M M M C G C G T A T T A G T A C A A G
III. A) Transcriptional Regulation: III. A. 1) Histone Modification Chemical modification of histone proteins in the nucleosome Nucleosome: DNA (black) wound around histone proteins (colors) Figure from Wikipedia entry for nucleosome
III. A) Transcriptional Regulation: III. A. 1) Histone Modification • Influences “density” of DNA packaging in chromosomes • Influences transcription • Cocaine & amphetamines (and other drugs) histone modification
III. A) Transcriptional Regulation: III. A. 3) Transcription Factors Transcription factor (regulatory protein) = protein or protein complex that enhances or inhibits transcription.
CREB: Transcription factor in neurons CREB (cyclic AMP Response Element Binding Protein) Spermatogenesis CA c. AMP Circadian rhythms Protein kinases Long-term memory Phosphorylation
1) Various factors initiate 2 nd messenger systems. 2) Second messengers activate CREB by phosphorylation. 3) Activated CREB acts as a transcription factor, inducing the expression of C/EBP genes. 4) C/EBP proteins act as transcription factors. http: //www. cellscience. com/reviews 6/CREB_long-term_memory. html
Some genes regulated by CREB
HPA Axis: Example of hormones & behavior 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 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/Brain. Briefings/stress. html
http: //www. amtamassage. org/journal/su_00_journal/images/body 2. jpg
III. B) Editing Gene Regulation III. B. 1) Alternative RNA Splicing Different exons are spliced together to give different polypeptide blueprints RNA transcript before editing: exon 1 intron 1 exon 2 exon 3 intron 2 exon 4 m. RNA after editing: Polypeptide Blueprint 1 exon 3 intron 3 exon 4 exon 1 exon 2 intron 4 exon 3 exon 5 m. RNA after editing: Polypeptide Blueprint 2
III. B) Editing Gene Regulation III. B. 1) Alternative RNA Splicing • Varies among species. • Possible reason why number of human genes is so small. • Examples = Amyloid Precursor Protein (APP) gene, tau proteins • Is common in the human brain.
RNA splicing: Tau proteins
III. A. ) Pre-translational Epigenesis III. A. 1) RNA Interference: • Definition: A short sequence of single-stranded RNA (“i. RNA”) and a complex of proteins and enzymes (“silencing stuff”) binds with m. RNA and cleaves it. • Result: Decreases the “dimmer switch” by reducing translation. • No known human behavioral examples. • Important method in neuroscience; potential therapeutic intervention. See http: //www. nature. com/focus/rnai/animations/animation. htm for animated explanation.
III. A. ) Pre-translational Epigenesis III. A. 1) RNA Interference: i. RNA = + Interfering Stuff = Forms interfering complex Binds to m. RNA Cleaves m. RNA See http: //www. nature. com/focus/rnai/animations/animation. htm for animated explanation.
RNA Interference (double stranded RNA) (short interfering RNA) (RNA-induced silencing complex) http: //www. nature. com/horizon/rna/background/figs/interference_f 1. html
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
Epigenesis and Development 1. Zygote (fertilized egg) undergoes massive demethylation stem cells 2. Stem cells become slightly differentiated by various mechanisms (methylation, histone modification, and many others) but can still give rise to a number of different tissues. 3. These cells become further differentiated into tissue cells (e. g. , bone, muscle, neurons, liver cells) 4. Once a cell becomes fully differentiated in 3, it cannot become undifferentiated.
The developmental potential and epigenetic states of cells at different stages of development. Hochedlinger K , Plath K Development 2009; 136: 509 -523 NOTE: adapted from Waddington (1957)
Epigenesis and Development Example: Mammalian Sexual Development 1) Typical Course = Female 2) Males = “Masculinized” Females 2. a) 7 th week: SRY gene (sex-determining region of the Y chromosome) “turns on” 2. b) SRY protein acts as a transcription factor, influencing the expression of many other genes 2. c) testes develop 2. d) testes produce large amounts of androgens masculinization
http: //www. ncbi. nlm. nih. gov/disease/SRY. html
Homeobox Genes
Homeobox & Hox Genes (Drosophila and Mus) http: //www. people. virginia. edu/~rjh 9 u/homeo. html
Homeobox & Hox Genes (Drossophila, Mus & Homo) http: //universe-review. ca/F 10 -multicell. htm
Development (Drosophila and Homo) http: //universe-review. ca/F 10 -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/Brain. Briefings/hox_genes. html
More examples of 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/Brain. Briefings/ 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/ Brain. Briefings/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/Brain. Briefings/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/Brain. Briefings/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/Brain. Briefings/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. , FOXP 2 may influence language; ASPM & Microcephalin may influence head circumference.
Anamika et al. (2005) BMC Genomics, 9: 625. Protein kinase evolution in humans and chimps. Green = chimp specific Black = common Important question: How much green and how much black?
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