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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 controls.

• 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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Figure 11.4

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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

8Figure 11.4

Figure 11.3

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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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HemoglobinEach globin surrounds an iron-containing

heme group

Figure 11.1

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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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Organization of Globin Genes in the human genome

ᵋ

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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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Globin Chain Switching

Figure 11.2

17Figure 11.8

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

Chromatin Remodeling

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Chromatin RemodelingSpecific Chemical modifications that bind to histones and

DNA are:- Acetyl group- histones- Methyl groups- histones and DNA- Phosphate groups- histones

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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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Disorders of Chromatin Remodeling

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Alternate splicing help to greatly expand the gene number

Maximizing Genetic Information

Figure 11.9

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MicroRNAs : • class of noncoding 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

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RNA interference (RNAi)Technology for selective silencing of gene

expression

Dicer

Hydrogenbond

Proteincomplex

miRNATarget mRNA

Degradation of mRNA

OR

Blockage of translation

29Figure 11.11Figure 11.8

Maximizing Genetic Information

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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

33Figure 11.11Figure 11.8

Maximizing Genetic Information