Regulation of gene expression 2 Flashcards
Transcirptional activators have both
DNA binding domains and activation domains
An example of the activation domain is the:
Glucocorticoid receptor: metabolism, development, and immune responses
An exampled of the DNA binding domain is:
TF specificity protein 1- apoptosis, differentiation, DNA damage, etc.
Eukaryotic transcriptional activators may have more than 1 activation domain. What is a flexible domain?
Allows interaction between neighboring factors even if their relative positions on the DNA are shifted
What is the process by which the Glucocorticoid receptor enacts upon target tissue?
GCR binds cortisol in cytosol
Heat shock protein dissociates from receptor hormone complex, exposing nuclear localization signal
Receptors form dimer to be transported to nucleus
Inside of nucleus receptor binds glucocorticoid response element
–>Its transactivation domain binds mediator proteins and activates transcription
In the steroid-thyroid hormone receptor:
Usually exists as heterodimer (TR + RXR)
Without TR dimer forms corepressor and inhibits transcription
In presence of TR coactivator is triggered to bind- activates transcription
*Lack of hormone or its receptor can result in a disease
Nuclear receptor mutations can affect its:
ligand binding- there will be no effect in the presence of ligand
Coactivator binding- results in constituative binding of corepressor
*Mutations in VDR that disrupt DNA binding domain result in alopecia
What are locus control regions (LCRs)?
Recruits chromatin remodeling factors and creates open chromatin
LCRs associated with proteins
Control the expression of cluster genes
–>LCRs control the expression of Globin gene family
Insulators are DNA sequences that, in association with proteins, can act as:
Enhancer blockers- when located between enhancer and promoter
Barriers- when located between silencer and promoter
Mutations in LCRs can be associated with
Thalassemias
Gene amplification can be used to:
increase the amount of gene product by increasing the number of genes available for transcription- these amplified genes provide multiple sites for transcription
Ex: rRNA and tRNA; also is a frequent genetic abnormality in human cancer cells and consists of multiple extra copies of a specific region of DNA
The most common types of genes amiplified are:
oncogenes
drug resistance genes
Gene amplification has been detected in patients receiving:
Methotrexate to treat cancer
–>malignant cells develop resistance by increasing number of genes for dihydrofolate reductase, the target for methotrexate
Gene rearrangement can occur in three different mechansisms:
Recombination
ex: VDJ
Class switching
ex: antibodies
Alternative splicing
ex: exon skipping
Alternative splicing in the calcitonin gene produces 2 different mRNAs for 2 different proteins:
Calcitonin in thyroid cells- reduces plasma calcium levels
–>increased level of calcitonin in is associated with thyroid nodule carcinoma
Calcitonin gene related protein(CGRP)- in neurons acts as a vasodilator and pain transmitter
–> increased levels of CGRP have been associated with migranes
Abnormal splicing diseases are:
When mutations in splicing regulatory sequences result in disease
ex: Taupathies => disease of CNS that show accumulation of protein tau.
–>studies show mutations in tau gene to be associated with dementia and parkinsons
Another example of abnormal splicing is:
LDL receptor => hypercholesterolemia
Well known example of RNA editing
ApoB mRNA
Gene expression can also be regulated through the control of mRNA degradation:
Nonsense-mediated degradation: triggered when ribosome stops before reaching an original STOP codon
mRNA turnover: most mRNA undergoes progressive shortening of poly A tail. loss of tail lead to rapid degradation. –>degradation catalyzed by cytoplasmic exosome from 3’ end.
ARE-mediated decay: occurs from mRNAs containing A+U rich elements. Limits halflife of mRNA to prevent overexpression of specific proteins.
Nonstop decay: assists in degradation of mRNA that lacks translation termination codon.
Regulation of gene expressio can also occur via regulation of translation:
Regulatory proteins: stabilize mRNA and allow more cycles of translation
Rare codons: regulate rate of translation by having fewer copies of tRNA in the cell
miRNA: can target mRNA for degradation
Another way gene expression can be regulated via translation is through its initiation:
Ferratin (main iron storage protein in cell) contains iron response element (IRE) near 5’ end of mRNA
Low iron => IRE-BP prevents translation
High iron => IRE-BP binds iron and dissociates from IRE = translation of ferritin mRNA
The final way in which eukaryotes can reuglate gene expression is via the stability of mRNA
Transferrin receptor takes up transferrin (iron transporter in blood)
intracellular iron low => IRE-BP binds to IRE and prevents degradation of mRNA = more receptors
intracellular iron high => IRE-BP binds iron = release of mRNA =mRNA is degraded = less receptors
