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PATH3309 > 4 - Regulation of Gene Expression > Flashcards

4 - Regulation of Gene Expression Flashcards

1
Q

Gene expression

A
  • The process by which the information stored in our DNA is converted into a functional product (protein)
  • The expression of specific genes determines the identity of the cell
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2
Q

Mechanisms of regulation

A
  • Transcription
  • Post-transcription
  • Translation
  • Post-translation
  • Epigenetic
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3
Q

Cis-regulating elements

A

DNA in the vicinity of the structural portion of a gene that are required for gene expression

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4
Q

Trans-activating factors

A
  • Factors that bind to the cis-acting sequences to control gene expression (transcription factors)
  • Help position RNA polymerase at promoter site and initiate transcription (positive regulators of gene expression)
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5
Q

Transcription factors

A
  • Specific
  • Combination of transcription factors is necessary to initiate transcription of a gene.
  • Presence/availability of the required transcription factors regulate transcription initiation
  • Transcription factors are also themselves regulated by signals produced from other molecules
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6
Q

Spatial regulation

A

expressed in a tissue-specific manner

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7
Q

Temporal regulation

A

expressed at a specific time in development

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8
Q

Activity regulation

A
  • Protein modification (e.g. phosphorylation)
  • Activated by ligand binding
  • May be sequestered until an appropriate environmental signal allows it to interact with the nuclear DNA
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9
Q

Transcription factor binding sites

A
  • Bind to enhancer
  • Certain proteins assist in bending the DNA so that the enhancer is near the promoter
  • Transcription factors and other proteins attach to form an initiation complex, transcription now begins.
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10
Q

What is transcription elongation tightly coupled to

A

RNA processing (post transcriptional regulation)

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11
Q

Post-transcriptional regulation

A
  • Further processing of the RNA
  • The transcript is capped (5’ cap) and poly-adenylated (poly A tail)
  • RNA splicing then removes the non-coding parts of the transcript (introns) so that only the coding sections (exons) remain
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12
Q

Function of 5’ cap

A

Stabilize and mark transcript as mature to prevent degradation

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13
Q

Function of poly A tail

A

Helps ribosome attach to begin translation

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14
Q

Alternative splicing

A
  • Post-transcriptional regulation
  • Variations in mRNA (and proteins)
  • One gene can encode for more than one protein
  • Grants genetic diversity
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15
Q

Example of alternative splicing

A

Calcitonin is alternatively spliced in the thyroid and neurons (same gene, different protein)

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16
Q

Varying longevity of mRNA

A
  • Can last a long time and can continue to produce protein in the absence of DNA
  • E.g. mammalian red blood cells eject their nucleus but continue to synthesise haemoglobin for several months
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17
Q

Examples of post transcriptional regulation

A
  • 5’ capping and poly A tail
  • Alternative splicing
  • Varying rate of transport of mRNA through
    the nuclear pores
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18
Q

Degradation of mRNA

A
  • Ribonucleases destroy mRNA
  • Hormones stabilise certain mRNA transcript
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19
Q

miRNA

A
  • Micro RNAs
  • Inhibit translation
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20
Q

rRNA

A
  • Ribosomal RNAs
  • Invloved in mRNA translation
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21
Q

lincRNA

A
  • Long non coding RNAs
  • Protein scaffolding, guidance, mRNA stability
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22
Q

circRNA

A
  • Circular RNA
  • RNA binding protein and miRNA decoy
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23
Q

miRNA and post-transcriptional regulation

A
  • 22bp ssRNA
  • Can bind to protein complexes to form RNA‐Induced Silencing Complexes (RISC) to inhibit mRNA translation
  • RISC binding interferes with translation, resulting in down-regulation of gene expression
24
Q

Regulation of Gene Expression via translational control

A
  • Physical regulation (blockage)
  • Initiation factors
  • tRNA heterogeneity and codon usage bias
25
Q

Physical regulation (blockage)

A

Proteins (even miRNA) that bind to mRNA (via specific sequences) can prevent ribosomes from attaching and thus prevent translation of
certain mRNA molecules

26
Q

Initiation factors

A
  • These bind to and help assemble the ribosome complex to initiate translation
  • The availability of these factors are also regulated and are produced when certain
    proteins are needed
27
Q

tRNA heterogeneity and codon usage bias

A
  • The relative abundance of tRNA can vary between tissues
  • Coupled with preferential use of specific codons, this can regulate the rate of
    translation
28
Q

Post-translational modifications

A
  • Increases the functional diversity of the proteome
  • Molecular chaperones help guide the folding of many proteins
  • Post-translational modifications can result in protein activation
29
Q

What do translational modifications include

A
  • Covalent addition of functional groups or proteins
  • Proteolytic cleavage of regulatory subunits
  • Degradation of entire proteins (proteasomes bind ubiquitinated proteins and degrade them)
30
Q

Proteome complexity

A

The myriad of different post-translational modifications exponentially increases the complexity of the proteome relative to both the transcriptome and genome

31
Q

Name 3 examples of post translational modifications

A
  • Phosphorylation: phosphate group, usually to Ser, Tyr, Thr or His
  • Glycosylation: carbohydrates, usually Asn, hydroxylysine, Ser, or Thr
  • Methylation: methyl group, usually at Lys or Arg residues
32
Q

Epigenetics

A

Alterations that cause a change in gene expression but doesn’t involve any changes in the DNA sequence

33
Q

Examples of epigenetic regulation

A

DNA methylation and histone modification

34
Q

DNA methylation

A
  • Addition of a methyl group to cytosine at CpG islands (regions of the genome with high frequency of CG sites)
  • Inhibits transcription by preventing access to promoters
  • Plays a role in silencing tissue-specific genes
35
Q

Histone modifications

A
  • Acetylation or deacetylation
  • Histone acetyltransferases, histone deacetylases (HDACs) and others regulate these modifications
  • Some cancer cells overexpress or aberrantly recruit HDACs
  • HDAC inhibitors are valuable cancer therapeutics, they can increase transcription, and lead to cell cycle arrest and apoptosis
36
Q

Some cancer cells overexpress or aberrantly recruit HDACs

A

Hypoacetylation, condensed chromatin structure and reduced transcription

37
Q

Acetylation

A

Associated with euchromatin (“open for transcription“ or active)

38
Q

Deacetylation

A

Associated with heterochromatin (“closed“ or tightly wound DNA)

39
Q

Are epigenetic alterations heritable

A

Yes

40
Q

Cancer

A
  • Cancer cells reproduce without restraint and colonise foreign tissues
  • Most cancers derive from a single abnormal cell (epigenetic or genetic)
  • Single mutation is not enough to cause cancer
41
Q

Multiple stages of tumour development

A
  • Initiation (genetically abnormal cell)
  • Promotion (selective clonal expansion)
  • Progression (additional mutations affecting polarity and communication)
  • Invasion and metastasis (Invasion and colonisation of
    secondary site)
42
Q

Gene expression and cancer

A
  • Cancer is a disease of dysregulated gene expression that imparts a survival advantage to the cell
  • Alterations can occur at all levels of gene expression (e.g. histone acetylation, activation of transcription factors)
43
Q

Proto-oncogenes

A
  • Genes that stimulate cell growth and division in normal cells
  • Become oncogenes through gain of function mutations
44
Q

Tumour suppressor genes

A
  • Genes that inhibit cell division in response to DNA damage and allow repair to occur
  • Usually lose their function in cancer (loss-of-function)
45
Q

Epithelial-mesenchymal transition (EMT)

A
  • The process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties
  • Occurs naturally (e.g. tissue repair), but also important for initiation of metastasis in cancer
46
Q

How do cells lose control of cell growth and/or death?

A
  • Proto-oncogene gain of function mutations
  • Tumour supressor gene loss of function mutations
47
Q

How do cells lose cell polarity and miscommunicate?

A

Epithelial-mesenchymal transition (EMT)

48
Q

What are the practical applications of studying gene expression in cancer?

A

Gene expression profiling

49
Q

Gene expression profiling

A
  • Capturing total gene activities, both increases
    and decreases, across a genome as patterns of gene expression
  • Allows us to define different subtypes of cancer based on their gene expression profiles
50
Q

What is gene expression profiling useful for

A
  • Treatment selection (identify which specific pathways are deregulated in the tumour and treat with therapies that target that pathway)
  • May predict cancer patient survival and prognosis
  • Increasing understanding the molecular pathways that underlie cancer
51
Q

Gene expression profiling and treatment selection in breast cancer

A
  • A heterogeneous group of cancers with characteristic molecular features, prognosis and responses to available therapy
  • three types based on gene expression profiling
52
Q

Three types of breast cancer classifications

A
  • Luminal (ER and PR positive, hormonal intervention)
  • HER2+ (ERBB2 overexpression, Anti-HER2
    therapy)
  • Basal like (Triple negative, Most difficult to treat)
53
Q

Inter-tumour heterogeneity

A
  • Variation between patients
  • Different morphology types, expression subtypes, or gene expression
54
Q

Intra tumour heterogeneity

A
  • Variation within a tumour
  • Different morphology AND different at the molecular level (tumour subpopulations)
55
Q

Why do cancer cells frequently display startling heterogeneity for various traits related to tumourigenesis (e.g. angiogenic, invasive, and metastatic potential)

A

Clonal and cellular diversity for genetic and epigenetic alterations, Adaptive responses or fluctuation in protein levels and activity of signalling pathways

56
Q

Gene expression profiling in
myelofibrosis

A
  • Myelofibrosis is a bone marrow cancer where there is extensive scarring in the marrow that results in an inability to make blood cells
  • Myeloproliferative
    neoplasm
  • Diagnosis anad monitoring requires invasive bone marrow exam
57
Q

Benefits of gene expression profiling

A
  • Improved diagnosis, prognosis, treatment
  • Personalised medicine
  • Provides framework for testing targeted therapies

PATH3309 (26 decks)

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