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Control of Gene Expression Eukaryote (Gene expression regulates…
Control of Gene Expression
Eukaryote
Gene expression regulates development
Responsible for differences in cell types
Differentiation is driven by gene switching
Difference between one cell type and another is primarily in the range of genes that are active in each cell
Gene expression control
Genes encode proteins and it is the proteins in the cell that dictate cell function
-The thousands of gene expressed in a particular ell determine what that cell can do.
Information from DNA to RNA to protein provides the cell with a potential control point for self-regulating its functions
Done by adjusting the amount and type of proteins it manufactures
Regulation of chromatin structure
Transcriptionally active chromatin is structurally distinct from inactive chromatin
Chromatin description
The DNA-protein complex which comprises eukaryotic chromosomes
Eukaryotic chromosomes
Linear DNA molecules associated with a large amount of protein
Chromatin is DNA wound around clusters of 8 histone proteins
known as octamer and linked together
Histones not only keep DNA organised, but regulate gene expression
RNA polymerase I resides in the nucleus
Heterochromatin
highly condensed form of chromatin
Dense packing of the heterochromatin make it difficult for cell to express genetic information coded int these regions
This material is generally not available for transcription
Euchromatin
Loosely packed chromatin.
Available for transcription
Packaging of chromatin
Dependent on histone proteins
Histone proteins have a high % lycine and arginine
Chromatin remodelling goes through a process called opening.
Vital to the proper functioning of all eukaryotic cells.
Histone acetylation/deacetylation
Histone acteylation is the addition of an acetyl group COCH3 to the histone tail
Enzyme is histone acteyl transferase
When lysine groups re acetylated they are neutralised and histone tail no longer being to neighbouring nucleosomes
Makes the structure less compact and more accessible to transcription
Deactylation removes the acetyl groups and this promotes folding
Positively charged tails of nucleosomal histone proteins probably interact with the negatively charged phosphates of DNA
Histone methylation
Histone methylation is the addition of a methyl group CH3 to the histone tail
This is associated with reduced transcription
Might block DNAs access to transcription factors
Histone acetylation might change electrostatic interactions within the chromatin to open up DNA and allow transcription
Addition of a phosphate group amino acid next to the methyl group have the opposite effect
DNA Methylation
The addition of methyl groups to certain bases in DNA
Associated with reduced transcription in some species
In genomic imprinting methylation regulates expression of either the maternal or paternal alleles of certain genes at the start of development
Imprinted genes violate the usual rule of inheritance that both alleles in a heterozyote are equally expressed insulin-like growth factor-2 paternal gene is expressed
Epigenetic inheritance
Chromatin modifications do not alter DNA sequence, they may be passed to future generations of cells
Inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance
Regulation of Transcription Initiation
Chromatin modifying enzymes provide initial control of gene expression by making a region of DNA either more or less able to bind the transcription machinery
Organisation of a typical eukaryotic gene
Associated with most eukaryotic genes are control elements.
Segments of noncoding DNA that help regulate transcription by binding certain proteins
Control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types
Introns:
Noncoding sequences that get their name from their intervening presence
Genes often have many introns that fall between the part of the gene that actually code for phenotype
Exons
Coding sequences that get their name from their expressed nature
Roles of Transcription Factors
Initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors
They cannot initiate transcription on their own
Set of proteins which must be assembled before transcription can begin
General transcription factors are essential for the transcription all protein coding genes
High levels of transcription if particular genes depend on control elements interactive with specific
Enhancers and specific transcription factors
Proximal control elements are located to the promoter
Distal control elements which are called enhancers maybe far away from a gene or even located in an intron
Activator is a protein that binds to an enhancer and stimulates transcription of a gene
Bound activators cause mediator proteins to interact with proteins at the promoter
Some transcription factors function as repressors inhibiting expression of a particular gene
Some activators and repressors act indirectly by influencing chromatin structure to promote or silence transcription
Transcription factors are regulated by signals produced from other molecules
Hormones activate transcription factors and thus enable transcription.
Therefore hormones activate certain genes
Post transcriptional regulation - RNA processing
Both 5' cap a modified guanine nucleotide and the poly(A) tail have been implicated as being involved in the regulation of translational efficiency and message stability
Facilitate the export of the mature mRNA from the nucleus-tracked
Help protect the mRNA from degradation by hydrolytic enzymes
Help ribosomes attach to the 5' end of the mRNA
mRNA degradation
Level of mRNA in cytoplasm often determines the level of encoded protein product.
Levels of mRNA are regulated by the rate synthesis, export and degradation
Degradation mRNA is one of the key processes that control the level of gene expression
Functional group of genes showed different rates of mRNA decay
mRNA encoding structural proteins have longer half life in cell - hours
mRNA encoding signalling proteins shorter - less than half hour
Differences are partially mediated by structural characteristics of transcripts
Sequences with 5' untranslated regions (UTRs) and 3' (UTRs) were the primary determinants of rapid mRNA decay
A-U rich more prone to decay due to affinity for ribonucleases
Alternative splicing
During RNA splicing exons are either retained in the mRNA or targeted for removal in different combination to create a diverse array of mRNAs from a single pre-mRNA.
This is known as alternative RNA splicing
At least 70% of the approx 30,000 genes in the human genome undergo alternative splicing.
On average given gene gives rise to 4 alternatively spliced variants - encoding a total of 90-100,000 proteins which differ in their sequence and therefor in their activities
Alternative RNA splicing
More that a dozen cancers and inherited diseases in humans are associated with abnormalities in alternative splicing
These abnormalities alter the abundance, location, or timing of a normally expressed mRNA isoform
Types of splicing alteration observed include
exon skipping
intron retention
alternative splice donor
acceptor sites
These give rise to different protein isoforms in different tissues
developmental states
Or disease conditions
Translation
Opportunity to control gene expression
Poly A tail and 5' cap are required for ribosome bending
In eggs many organisms translation is halted as mRNA lack polyA tail long enough to allow translation at appropriate time of embryo development cytoplasmic enzymes add tail
Algae mRNA stored until trigger such as light reactivates translation
Important function of the poly(A) tail is the stimulation of translation initiation.
This involves an interaction between the cytoplasmic poly(A)-binding protein (PABPC), covering the poly(A) tail.
The ranslation initiation factore IF4G bound to the 5 cap as part of the elF4f complex
Protein processing and degradation
Final opportunity for controlling gene expression is following translation
Polypeptides must often be processed to create functional proteins
They may be cleaved, acquire sugars or phosphate groups
Polypeptides often must be transported to specific destination in the cell to function.
Cell also degrades defective or damaged
To mark a protein for destruction the cell attaches the small protein, ubiquitin.
Protein complexes called proteasome recognise ubiquitin and degrade the tagged protein