Essential Molecular Biology (BIOC0007) Notes - Transcriptional Regulation and Translation
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Course
Essential Molecular Biology (BIOC0007)
Institution
University College London (UCL)
Explore Essential Molecular Biology at UCL. Navigate the intricacies of Transcriptional Regulation and Translation in this specialized resource tailored for Year 2 students. Uncover the molecular orchestration governing gene expression. These notes offer a humanized academic guide, deepening your c...
Transcriptional Regulation and Translation – Summary
Transcriptional Regulation
Regulation of Transcription
o Initiation of transcription
Assembly of general transcription factors at promotor – basal transcription machinery
o Activation of transcription
Additional transcription factors bind promotor upstream regulatory elements
o Activation of transcription at a distance – distal regulation
Elements that regulate transcription from a further distance = enhancer regions and distal
regulation
Not every gene has enhancer elements
Combination of different regulatory elements – allows regulation of transcription
o Tissue-specific, spatial, and temporal control
Regulation of a specific gene is coordinated to where and when it is needed – through
promotor-proximal elements and distal enhancers
Regulating initiation of eukaryotic gene transcription
o General transcription factors (GTFs) + mediator
+ chromatin acting enzymes
Transcriptional activators bind to
specific regions of the DNA (enhancer
regions)
Helps attract RNA polymerase
to the start of transcription
Further upstream from
promotor elements (TATA box)
Bound by activator proteins
Mediator complex interacts with
transcriptional activator proteins
Causing communication between activator proteins + polymerase + GTFs to
enhance level of transcription
Interacts with enhancer regions bound by activator proteins to enhance the level of
transcription
Chromatin acting enzymes – makes eukaryotic DNA more accessible
Chromatin opens up
DNA made more accessible for RNA polymerase II by chromatin re-modellers +
histone-modifying enzymes
o Allowing ability to regulate individual gene transcription – where and when its needed
Tissue-specific gene expression
o Transcription of albumin gene
Albumin gene
Core promotor – proximal elements bind to core
promotor
Control elements – upstream elements including enhancer region
o Expression of albumin in 2 tissue types
Liver – transcription of albumin at a high
level
Required activator proteins are
found in a high level in the liver
Brain – transcription at albumin at a low
(basal) level
,Transcriptional Regulation and Translation – Summary
Required activator proteins are found in a low level in the liver
o Achieved through availability of proteins in different tissue types
Proteins that bind to upstream control elements = regulatory transcription factors
Tissue specificity achieved through expression of correct combination of required activators
Transcription factor domains – a region with its own structure and function
o DNA binding domain
Recognises DNA binding site
o One or more activation (or repression) domains
Affects what needs to be done to upregulate transcription
Gene activation
o Hormone-dependent gene activation by dimeric nuclear receptors
When cortisol is not in cell – receptor is retained in cytoplasm by inhibitor binding to ligand
binding domain
When cortisol diffuses into the cell through plasma membrane – has a higher affinity to
ligand = replacing inhibitor allowing accessibility into nucleus DNA binding domain
binds to response elements allowing activation domain to stimulate transcription of
target genes
Transcription of protein encoding genes – highly regulated at different levels
o Initiation of basal level of transcription
GTFs in PIC in eukaryotes
Operons in prokaryotes
o Enhancement of basal transcription
Activators in prokaryotes and eukaryotes
o Tissue specificity
Presence of activators limited to certain tissues
o Processing of mRNA = pre-mRNA mature mRNA = 5’ cap, 3’ poly A tail, removal of introns
Epigenetics – another level of transcriptional regulation
o A series of reversible modifications to chromatin
Chemical modifications that alter levels of transcription globally
Chromatin changes can be inherited – by chromatin changes not DNA sequence changes
o Study of changes in regulation of gene activity and expression – independent of gene sequence
o Mechanisms
DNA methylation – at the level of the DNA helix
Histone modifications – DNA is condensed around histones forming chromatin
Non-coding RNA (ncRNA)
DNA methylation
o Addition of a methyl group to a cytosine on DNA
Cytosines normally before guanine = CpG – p = phosphate between nucleotides
One methyl group added per CpG
CpG island = regions of the genome that contain a large number of CpG dinucleotide repeats
o Tagging specific points on the DNA molecule with a methyl group
Controls X-chromosome inactivation and expression of imprinted genes – which are key
regulators in development
Represses the transcription of repeated sequences + prevents relocation of transposable
elements maintaining genomic stability
Marks the bodies of active genes – influencing on splicing
Regulates gene expression by repressing promotor activity
In eukaryotes:
o Promotor hypermethylation (lots of methyl groups) = silences genes
o Promotor hypomethylation (lack of methyl groups) = activates genes
o Interactions from methylation
, Transcriptional Regulation and Translation – Summary
Unmethylated DNA
Has open conformation – which is more accessible for transcription factors
Methylated DNA
Physically impedes binding of transcription factors
Methyl CpG binding proteins preferentially bind methylated DNA through their
methyl CpG binding domains (MBD)
o DNA methylated code is read by proteins that recognise regions of
methylated DNA = methyl-binding proteins with methyl binding domains
o Read the epigenetic code and act on it directly or recruit effector proteins
o Mechanisms of methylation
Maintenance methylation
Maintains methylation pattern already established on DNA
Important during development
Enzyme = DNMT1 = DNA methyltransferase 1
Steps
o Before replication
DNA is fully methylated at CpG dinucleotides
o During replication
New DNA strands are synthesised without methyl group
o After replication
Each new DNA molecule has methylation on one strand = hemi-
methylated
o Methyl transferase enzyme
Hemi-methylated DNA is recognised by methyl-transferase enzyme
– has specificity for hemi-methylated DNA = adds methyl groups to
unmethylated strand
o Resulting in fully methylated DNA
De novo methylation
Establishment of new methylation patterns by de novo methyltransferases
Enzymes = DNMT3a + DNMT3b = DNA methyltransferase 3a + 3b
o Directed to DNA by sequence specific DNA binding proteins
Occurs during early development – after removal of methylation after fertilisation
Imprinting
o In most genes – copies inherited from mother and father are equally expressed
o Genomic imprinting = epigenetic gene regulation that results in expression from a single allele in a
parent-of-origin dependent manner
Achieved through different methylation patterns + use of non-coding RNA
Maternal and paternally inherited alleles are differentially expressed
Silenced allele = imprinted allele
o E.g. lgf2 gene
Imprint is erased when making gametes then re-established according to the sex of the
individual
In eggs – imprints reset to maternal patterns even from genes from the father
In sperm – imprints reset to paternal patterns even from genes from the mother
Correct imprinting pattern is permanently established on zygote
o Imprinting disorders
When methylation patterns are not maintained correctly – results in overexpression of one
or both alleles
If mechanism effects expression – as there is only one active allele – there is nothing
to fall back on
Imprinted genes are often clustered on the same chromosome
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