Gene expression

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23 Terms

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What are transcription regulatory proteins?

recognize specific DNA sequences because of the surface features of the double helix (recognizes surface features) 

  • Complex arrangements that respond to a variety of signals that are interpreted and integrated 

  • Double helix features = major & minor groove 

    • Binds to the major grooves because it has the cis-sequences & other contact points 

  • Contain structural motifs  

  • Don't need to unwind DNA to read sequences 

  • In bacteria: transcription is controlled by 1 regulatory protein (and have operons) 

  • In eukaryotes: many proteins control transcription & can act over very long distances 

  • Single transcription regulatory proteins 

    • Single proteins can make the final decision as to transcribe or not 

    • Can form an entire organ by beginning a cascade of other proteins & cell-cell interactions 

      Ex: eyeless drosophila (eyes instead of legs form) 

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What are structural motifs

bind to the major groove based on the protein’s amino acid side chains (a recognizable, recurring 3D arrangement of secondary structure elements, such as helices and sheets, connected by loops)

  • Found in transcription regulators 

Common motifs:  

  1. Helix-turn-helix = 2 alpha helices with a recognition sequence 

  • Homeodomains are a type of helix-turn-helix 

  1. Zinc fingers = DNA binding proteins with a zinc (unique) moiety 

  • zinc can hold alpha helix and beta sheet together 

  • Zinc fills a two-alpha helix protein 

  1. Protein protruding loops =  

  1. Leucine zippers =  

<p><span>bind to the major groove based on the protein’s amino acid side chains&nbsp;(a recognizable, recurring 3D arrangement of secondary structure elements, such as helices and sheets, connected by loops)</span></p><ul><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Found in transcription regulators&nbsp;</span></p></li></ul><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Common motifs: &nbsp;</span></p><ol><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Helix-turn-helix = 2 alpha helices with a recognition sequence&nbsp;</span></p></li></ol><ul><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Homeodomains are a type of helix-turn-helix&nbsp;</span></p></li></ul><ol start="2"><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Zinc fingers = DNA binding proteins with a zinc (unique) moiety&nbsp;</span></p></li></ol><ul><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>zinc can hold alpha helix and beta sheet together&nbsp;</span></p></li></ul><ul><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Zinc fills a two-alpha helix protein&nbsp;</span></p></li></ul><ol start="3"><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Protein protruding loops = &nbsp;</span></p></li></ol><ol start="4"><li><p class="Paragraph SCXW54767880 BCX0" style="text-align: left"><span>Leucine zippers = &nbsp;</span></p></li></ol><p></p>
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What are cis-regulatory sequence

DNA sequences specify the time and place that each gene is to be transcribed when read by their specific bound transcription regulators 

  • DNA sequences recognized within the same molecule 

  • Control transcription and are upstream of the transcription initiation start point  

  • Positive regulators = activators 

  • Negative regulators = repressors 

  • Many protein regulators control a single gene (many regulator sequences within that gene 

  • DNA looping critical for proteins, sequences, and polymerase to interact 

    • “Complex switches” 

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What is the significance of DNA looping

DNA looping critical for complex switches to interact (it ISN’T LINEAR) 

  • Brings activators/repressors and sequences closer to the mediator and other TFs 

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Gene control region (GCR)

consists of activator (and co-activator)/regulatory sequence/associated proteins, promoter region/factors/RNA pol, gene, more reg. proteins (chromatin remodelers) 

  • Formed when a mediator is present and binds all the components together 

  • RNA pol. II then transcribes all coding genes & non-coding RNA genes

<p><span> consists of activator (and co-activator)/regulatory sequence/associated proteins, promoter region/factors/RNA pol, gene, more reg. proteins (chromatin remodelers)&nbsp;</span></p><ul><li><p class="Paragraph SCXW53437769 BCX0" style="text-align: left"><span>Formed when a mediator is present and binds all the components together&nbsp;</span></p></li></ul><ul><li><p class="Paragraph SCXW53437769 BCX0" style="text-align: left"><span>RNA pol. II then transcribes all coding genes &amp; non-coding RNA genes</span></p></li></ul><p></p>
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How do cells control their own proteins? (list and describe)

  • Transcriptional control = DNA to RNA transcript 

    • Controlled by DNA sequences (cis-regulatory sequences) near a gene upstream of the transcription initiation start point which are recognized by transcription regulator proteins 

  • RNA processing 

    • RNA transcript to mRNA 

  • RNA transport and localization 

    • mRNA being exported from the nucleus to the cytosol 

  • Translation control 

    • mRNA to protein 

  • Degradation control (both mRNA & protein) 

    • mRNA to inactive mRNA (degradation) or protein degraded into inactive protein 

  • Protein activity control (phosphorylation) 

    • Making a protein into active or inactive 

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How are cells specialized

  • Differences in RNA synthesis, transcription processing, and protein accumulation makes cells different and NOT DNA sequences 

  • Large array of proteins control expression of certain genes (activators/repressors), that act at different times during cell development 

    • Different combinations of proteins actions begin transcription of different genes 

      • Controlled by an intracellular “gene control network” that responds to the environment (epigenetics) 

  • Single transcription regulatory proteins can control transcription (more details on transcription regulatory proteins) 

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What do specialized cells have

Specialized cells

  1. Similarities in fundamental proteins (DNA/RNA polymerase, DNA repair enzymes, metabolic enzymes, etc) 

  1. Some proteins only made in the cells they function in  

  1. Levels of expression of active genes varies between cells 

  1. Alternative splicing and post-translational modifications occur in ALL cells 

  • De-differentiating cells = manipulation of certain master transcription regulators (Oct4, Sox2, & Klf4) causing the cell to de-differentiate to become stem cells 

    • The 3 TR are artificially expressed in fibroblasts -> lose specialization -> become pluripotent stem cells (used to treat diseases) 

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What are complex switches

control gene transcription in eukaryotes 

  • involve regulatory elements like enhancers and promoters, often located in non-coding regions, that control gene expression 

    • DNA looping critical for them to interact (it ISN’T LINEAR) 

  • Longer stretches of DNA looped out and spaced out 

  • More signals on one promoter 

  • More factors & proteins 

  • More developed in eukaryotes

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What is a promoter

Nucleotide sequence in DNA to which RNA polymerase binds to begin transcription

  • Stepwise assembly of many transcription factors at promoter site can change rate of initiation  

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What is an enhancer

Sequences regulatory proteins (transcriptional activators) must bind to in DNA (called enhancers) to help attract the general transcription factors and RNA polymerase II to the start point of transcription

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What is a mediator

30 subunit protein complex that acts as a bridge between all components of GCR (gene control region) 

  • When present and binding everything, then it forms the GCR 

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What are activator proteins

proteins that bind cis-regulatory sequences (formerly enhancer sequences) 

  • Can act at different steps during transcription initiation to promote it 

    • Binding to RNA pol. To continue transcription by loading elongation factors 

    • Releasing RNA pol. From promoter to start transcription 

    • Bring RNA pol. To sequence  

  • Can be far far away from the gene 

  • Function = to attract, position, and modify transcription factors to get close to RNA pol 

    • Helps recruit proteins, not only getting things started 

  • Can work synergistically to increase rate of transcription (works together) 

  • transcriptional synergy

  • DNA looping brings activator and sequence closer to the mediator and other TF 

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What is transcriptional synergy

where several DNA-bound activator proteins working together produce a transcription rate that is much higher than the sum of their transcription rates working alone 

<p><span>where several DNA-bound activator proteins working together produce a transcription rate that is much higher than the sum of their transcription rates working alone&nbsp;</span></p>
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What are repressor proteins

Proteins that further regulate transcription by using several mechanisms to ensure repression of transcription 

  • Do NOT compete with RNA polymerase 

  • Developmental regulatory genes are repressed after normal embryonic development 

    • Sometimes they’re re-expressed with tumors (oncofetal antigens) 

    Ex: CEA (colon cancer type & alpha-fetoprotein in liver cancer 

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What are some ways repressions can occur

Ways of repression:  

  1. Competitive DNA binding = repressor competes with activator 

  1. Masking the activation surface = activator/repressor are close enough to cover the other’s domain 

  1. Direct interaction with the general transcription factors = pushes activator away, preventing it from interacting 

  1. Recruitment of chromatin remodeling complexes = remodel chromatin to prevent binding 

  1. Recruitment of histone deacetylases = shutdown transcription by deacetylating 

  1. Recruitment of histone methyl transferase = methylates histones to silence transcription 

<p><span>Ways of repression: &nbsp;</span></p><ol><li><p class="Paragraph SCXW59155643 BCX0" style="text-align: left"><span>Competitive DNA binding = repressor competes with activator&nbsp;</span></p></li></ol><ol start="2"><li><p class="Paragraph SCXW59155643 BCX0" style="text-align: left"><span>Masking the activation surface = activator/repressor are close enough to cover the other’s domain&nbsp;</span></p></li></ol><ol start="3"><li><p class="Paragraph SCXW59155643 BCX0" style="text-align: left"><span>Direct interaction with the general transcription factors = pushes activator away, preventing it from interacting&nbsp;</span></p></li></ol><ol start="4"><li><p class="Paragraph SCXW59155643 BCX0" style="text-align: left"><span>Recruitment of chromatin remodeling complexes = remodel chromatin to prevent binding&nbsp;</span></p></li></ol><ol start="5"><li><p class="Paragraph SCXW59155643 BCX0" style="text-align: left"><span>Recruitment of histone deacetylases = shutdown transcription by deacetylating&nbsp;</span></p></li></ol><ol start="6"><li><p class="Paragraph SCXW59155643 BCX0" style="text-align: left"><span>Recruitment of histone methyl transferase = methylates histones to silence transcription&nbsp;</span></p></li></ol><p></p>
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What are cis-regulatory sequences

Gene regulatory proteins MUST BE BOUND to DNA (either directly or indirectly) at the cis-regulatory sequence to influence transcription of a target gene 

non-coding region that regulate transcription (where regulatory proteins bind)

  • Ex: enhancer

  • regulatory proteins = Activator or repressor 

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What are ways of chromatin/histone remodeling processes

Altering chromatin structure:  

  • Activators can also alter chromatin structure to promote transcription 

    • Makes underlying DNA more accessible to TFs, mediator, and RNA pol. 

      • Needs to be accessed for transcription to happen 

  • Mutant proteins block activators 

Histone  

  • Mutant proteins block transcription of histones 

Possible ways:  

  1. Nucleosome sliding allows access of transcription machinery to DNA 

    • Refold and open up 

  1. Transcription machinery assembles on nucleosome-free DNA 

    • Unwinding and disassemble nucleosome (removing the nucleosomes)

  1. Histone variants allow greater access to nucleosomal DNA 

    • With histone chaperons 

    • replacing the normal histones, with varients that allow for greater access

  1. Specific patterns of histone modification destabilize compact forms of chromatin and attract components of transcription machinery 

    • Via histone modifications 

<p>Altering chromatin structure: &nbsp;</p><ul><li><p class="Paragraph SCXW171740901 BCX0" style="text-align: left">Activators can also alter chromatin structure to promote transcription&nbsp;</p><ul><li><p class="Paragraph SCXW171740901 BCX0" style="text-align: left">Makes underlying DNA more accessible to TFs, mediator, and RNA pol.&nbsp;</p><ul><li><p class="Paragraph SCXW171740901 BCX0" style="text-align: left">Needs to be accessed for transcription to happen&nbsp;</p></li></ul></li></ul></li></ul><ul><li><p class="Paragraph SCXW171740901 BCX0" style="text-align: left">Mutant proteins block activators&nbsp;</p></li></ul><p class="Paragraph SCXW171740901 BCX0" style="text-align: left">Histone &nbsp;</p><ul><li><p class="Paragraph SCXW142667763 BCX0" style="text-align: left">Mutant proteins block transcription of histones&nbsp;</p></li></ul><p>Possible ways: &nbsp;</p><ol><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Nucleosome sliding allows access of transcription machinery to DNA&nbsp;</p><ul><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Refold and open up&nbsp;</p></li></ul></li></ol><ol start="2"><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Transcription machinery assembles on nucleosome-free DNA&nbsp;</p><ul><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Unwinding and disassemble nucleosome&nbsp;(removing the nucleosomes)</p></li></ul></li></ol><ol start="3"><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Histone variants allow greater access to nucleosomal DNA&nbsp;</p><ul><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">With histone chaperons&nbsp;</p></li><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">replacing the normal histones, with varients that allow for greater access</p></li></ul></li></ol><ol start="4"><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Specific patterns of histone modification destabilize compact forms of chromatin and attract components of transcription machinery&nbsp;</p><ul><li><p class="Paragraph SCXW113003077 BCX0" style="text-align: left">Via histone modifications&nbsp;</p></li></ul></li></ol><p></p>
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Why does X-inactivation occur

There is a dosage compensation in females (sometimes XXY males) because males only have 1X while females have 2X (one must get shut off) 

  • Mutations that interfere are lethal 

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What is transcription inactivation

X chromosome in somatic cells are dosaged compensated by X-inactivation 

  • Done to achieve dosage compensation (reduce X expression in females) 

  • Maintained through replication and cell division 

  • Early in cell development, one X in females is randomly condensed into heterochromatin (via Xist) and never recovers (not necessarily organ specific) 

    • Some cells will express the maternal X and others the paternal X 

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How does transcription inactivation occur?

  • XIC is found in the middle of the X chromosome (X-inactivation center) 

    • Both X chromosomes will have an XIC (only one will express Xist RNA = barr body) 

  • Xist RNA will ONLY be expressed by the inactive X (not as a protein) and coat the chromosome -> driving it into a heterochromatin formation 

    • 15-20% of genes at the tips of the chromatin loops remain active 

  • Histone variant with many modifications makes transcription of the inactive X virtually impossible 

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How are females mosaic

Because of randomly inactivated Xs 

  • Reversed during germ cell formation, so haploid germ cells have an active X 

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What is oncofetal antigens

Oncofetal antigens = re-expressed developmental regulatory genes, after normal embryonic development, resulting in tumors 

Ex: Carcinoembryonic antigen (CEA) in certain colon cancers & alpha-fetoprotein in liver cancer