Control of Gene Expression - San Diego Miramar …faculty.sdmiramar.edu/bhaidar/bhaidar 210A web...
Transcript of Control of Gene Expression - San Diego Miramar …faculty.sdmiramar.edu/bhaidar/bhaidar 210A web...
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Control of Gene Expression(Learning Objectives)
• Explain the role of gene expression is differentiation of function of cells which leads to the emergence of different tissues, organs, and organ systems despite the fact that all cells have the same DNA.
• Recognize the difference between house-keeping genes and cell-specific genes, using the example of the pancreas and its cells
• Explain the role of gene duplications and transposition in generating families of genes that carry similar but not identical function, using the example of hemoglobin. Define the term pseudogene.
• Explain the advantage to humans to having members of the globin gene family differentially gene expression during the embryonic, fetal, and adult stages.
• Learn the five primary levels of control of gene expression by name, sub-cellular location, and mechanism: Chromatin re-modeling or packing, transcription factors, alternative splicing, micro-RNAs and RNA interference, and the post translational modifications.
• Recognize the mechanisms and modifications that maximize the number of proteins that can be generated from a more limited number of human genes.
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Control of Gene Expression(Outline)
• Same DNA … different cells• House-keeping genes and cell-specific genes• From a stem cell to progenitor cells and their daughters.
Example: Pancreatic cells• Duplications and transposition- gene families advantageous to organisms
Example: Globin genes (embryonic, fetal, and adult) • 5 primary levels of control
o Nuclear: chromatin remodeling (epigenetic factors), transcription, and post transcription
o Cytoplasmic: mRNA and protein synthesis, post-translational• Maximizing number of proteins produced from a fixed number of genes
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Important facts• Individuals vary in absolute level of gene
expression• Gene expression changes over the life time of
individuals• Environmental factors can impact gene
expression by modifying the chromatin structure
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Changes in gene expression may occur over time and in different cell typesThis may occur at the molecular, tissue, or organ/gland level
Gene Expression Through Time and Tissue
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Gene Expression
Cells express 3-5% of their genes
House-keeping genes- all the time
Genes turned on or off- internal and external signals
Genes turned on only in some cell types not others while others are permanently shut down
(Highly specialized nerves or muscle)
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Pancreas
The pancreas is a dual gland
- Exocrine part releases digestive enzymes into ducts
- Endocrine part secretes polypeptide hormones directly into the bloodstream
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Ancient Genomic Structural Events
- Transposition: a genomic eventcertain sequences jump about the genome
Transposon is a single jumping sequence
- Repeated DNA sequences and multiple copies of certain genes. (example; globin genes)
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Hemoglobin
Adult hemoglobin has four globular polypeptide chains
- Two alpha (α) chains = 141 amino acids
- chromosome 16
- Two beta (β) chains = 146 amino acids
- chromosome 11
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Pseudogenes have accumulated too many mutations and produce no functional proteins
They are transcribed but are not translated
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Members of both the α and β families are expressed during the developmental stages: embryonic, fetal and/or adult
The embryonic and fetal hemoglobins have higher affinity for oxygen than do adult forms, ensuring transfer of oxygen from mother to developing fetus.
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Globin Chain Switching
Subunits change in response to oxygen levels
Subunit makeup varies over lifetime- Embryo = Two epsilon (ε) + two zeta (ζ)
- Fetus = Two gamma (γ) + two alpha (α)
- Adult = Two beta (β) + two alpha (α)
- The adult type is about 99% of hemoglobins by four years of age
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Control of Gene expression
5 primary levelsNuclear levels• Chromatin packing• Transcriptional level• Post-transcriptional level
Cytoplasmic levels• Translational level • Post-translational level
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Control of Gene ExpressionNuclear level controls
1) Chromatin remodeling = “On/off” switch2) Transcription Factors3) Alternative splicing
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– Nucleosomal beads of chromatin: DNA and histones“Beads on a string”
– Chromatin packing is the degree of nucleosome coiling– Histones play major role in gene expression
Expose DNA when it is to be transcribed shieldit when it is to be silenced
Specific Chemical modifications that bind to histones and DNA - Acetyl group- histones- Methyl groups- DNA
Chromatin Remodeling
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Histonetails
Amino acidsavailablefor chemicalmodification
DNAdouble helix
Histone tails protrude outward from a nucleosome
Acetylation of histone tails promotes loose chromatinstructure that permits transcription
Unacetylated histones Acetylated histones
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Epigenetic changesChanges to the chemical groups that associate with DNA that are transmitted to daughter cells after cell division
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Levels of control of gene expression include:
• Chromatin “remodeling” packing (Epigenetic)
• Transcription• RNA processing:
efficiency & alternative splicing
• RNA stability-microRNAs• Translation• Protein modifications• Protein degradation
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Alternative RNA splicingRegulates coding sequence of mRNA
PrimaryRNAtranscript
DNA
or
Exons
RNA splicing
mRNA
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Alternate splicing help to greatly expand the gene number
Maximizing Genetic Information
Figure 11.9
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• Proteins discrete structuraland functional regionscalled domains.
• Different exons code for different domains of a protein.
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- Efficiency of processing - Transport of mRNA to nucleus- Stability of mRNA
Post -Transcriptional Control
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Post-translational modifications- Protein cleavage to get two products- Addition of sugars and lipids to create
glycoproteins and lipoproteins
Maximizing Genetic Information
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Post-translational modifications
To produce functional proteins
- enzymatic cleavage - chemical modifications- transport to the appropriate destination
Improperly modified proteins are promptly degraded
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Dentinogenesis imperfecta- Caused by a deficiency in the two proteins DPP and DSP- Both are cut from the same DSPP protein
Maximizing Genetic Information
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Several groups:MicroRNAs (miRNA)- inhibit translation of same RNASmall interfering RNA (siRNA)- inhibit translation of other RNAsLong non-coding RNA (lncRNA)- variety of functions act in
cytoplasm and nucleushttp://www.whatisepigenetics.com/non-coding-rna/
When a interfering RNA binds to a “target” mRNA, it prevents translation
• Specific degradation of an mRNA • Specific blocking of translation
The human genome has about 1,000 distinct microRNAs that regulate at least 1/3rd of the protein-encoding genes
Role of Non-coding interference RNAs
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MicroRNAs : • class of non-coding RNAs• 21-22 bases long• The human genome has about 1,000 distinct
microRNAs• regulate expression of at least 1/3rd of the protein-
encoding genes
Interfere with gene expression by binding to a specific mRNA
- Degradation- Blocking translation
MicroRNAs