SCIE1106 Lecture Notes - Lecture 24: Fmr1, Fragile X Syndrome, Premature Ovarian Failure
L25 Eukaryote Gene Expression 2
• Understand diff facets of transcriptional control
• Realise that transcription factors bind
sequentially
• Intron-exon splicing
• DNA methylation, epigenetic regulation,
morphogen, TF, trans-acting, promoter,
regulatory sequences, cis-acting, UTR =
untranslated region
A modification to DNA
DNA methylation
• May silence genes in eukaryotes, gene silencing =
a type of gene regulation
o Eg DNA CpG methylation (CpG)
o Done by DNA methyltransferases DNMT
o Is symmetrical, occur on both strands
black = methylated CpG, chunks methylated = prevents
transcription factors from binding, genes aren’t
transcribed (off)
DNA methylation + Mis methylation
• Leads to fragile X syndrome
• Genetic/inherited condition (1/1500 to 1/4000
in males, 1/2500 to 1/8000 in females)
• Males have higher chances
• Learning disabilities, cognitive impairment,
autism, Parkinsonism, premature ovarian failure
• Cytologically, the fragile site on X-chromosome
cause breaks in vitro
• Fragile site= not as condensed, easily break off
DNA methylation on FMR1 gene + Fragile X Syndrome
• FMR1 gene = Fragile X mental retardation 1
o Encodes a protein found in the brain,
essential for normal cognitive
development + female reproductive
function
• FMR1 gene mutation = leads toxpansion of a CGG
triplet repeat (CGG CGG CGG etc) withtin the
FMR1 gene, usually from 5/40 copies to >200
copies
• CGG repeats/expansions, causes methylation +
silencing/ turn off of the FMR1 gene
o lack of FMR protein
o disrupts nervous system fx, leads to
complications of Fragile X syndrome
Epigenetic regulation/modifications + Eukaryote genes
• heritable but
• not due to changes to DNA nt sequence
o eg DNA methylation
o Histone modifications (HAT,HD)
How do cells with the same genes, differentiate to perform
completely different functions? Regulation of gene
expression
Gene expression
• Process by which info, from a gene, is used in the
synthesis of a functional gene product
o Proteins, tRNA, rRNA, regulatory RNA
•
Prokaryotic genes
• often polycistronic – encode more than 1 protein
• organised in operons – e.g Lac Operon
• few shared regulatory elements, simple
promoters
Eukaryotes have 3 RNA pol working in the nuclues
1. RNA pol I encodes 5.8S , 18S, 28S rRNA genes
2. RNA pol II transcribes/encodes
o all protein-coding genes (nuclear genes,
not the ones in mt/cp (cause they
bacteria)
o Small nucleolar RNA genes (snoRNA)
o Small nuclear RNA (snRNA) genes
o
snoRNA – guide chemical modifications
of RNAs (tRNA, rRNA, snRNA)
o
snRNA – help mRNA splicing – guide to
splice, using bp
3.
RNA pol III encodes
o tRNA genes
o 5S rRNA genes
o some snRNA genes
o genes for other small RNAs
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Eukaryotic genes (plants,animals,protists,fungi) p9
Has
1. Core promoter
a. determine transcription start site
b. determine direct binding of RNA pol II
i. eg TATA box in rapidly
transcribed genes (TATA box is
found in highly expressed genes
in eukaryotes
ii. TATA allows transcription to
occur, starting transcription
2. Transcriptional control regions
a. Promoter proximal Elements
i. Close to transcriptional START
site (within 200bp)
ii. Upstream/downstream of
transcriptional start site in
animal/mammalian/eukaryotic
genes
b. Distal promoter elements –
Enhancer/Repressor elements
i. Far upstream/downstream of
transcriptional start site/ inside
the introns
• Both Promoter proximal elements/ distal
promoter elements are similar, they are cis
elements that mediate cell type specific
expression + activate transcription.
• Composed of short DNA elements, that bind
activating TF proteins, sequences can be inverted
and are still functional
• TF may downregulate/upregulate gene
expression
Cis acting elements/ Trans acting factors
• Sequence motifs on a DNA which proteins can
bind to are called cis acting elements
o Core promoter elements
o Proximal promoter elements
o Enhancer elements
o Basically, trans-acting factors bind to Cis
acting factors
o Cis – acting from the same molecule, intra
molecular
• Proteins bind and act through these sequences
o Aka Transcription factors
o Trans – acting from a different molecule,
inter molecular
Morphogen gradients
• Drive the process of differentiation of
unspecialised stem cells into different cell types
• Morphogen = non-uniform distributed signalling
molecule (morphogen- a class of proteins)
o Regulates pattern formation during
development
o Regulates pattern formation during
differentiation
• Morphogens establish positions of the various cell
types within a tissue
• Diffuse from source cells, into surrounding
embryo tissues forming a concentration gradient
o Determines cellular response
o Determine cell-cell contact/ hormone
regulations as well
•
• highly expressed at the dark side
• e.g Bicoid – a TF, acting as a morphogen, during
Drosophila fruit fly’s embryogenesis
• Bicoid concentration determine development
along the anterior to posterior axis
• Low conc = turned off, high conc =turned on
•
• (right), Bicoid deficient, development is different
to the left one, aka Bicoid minus, no gradient
TF + Gene expression
• TF – the main form of gene regulation, done by TF
proteins
o TF determines if a gene is turned on/off
o TF modulates the gene expression’s level
1. must have DNA binding domain DBD, that binds to
cis acting sequences of DNA
o recall cis acting elements (regulatory
elements, enhancer elements, promoter
elements)
2. Signal sensing domain SSD
o They perceive signals- may
activate/deactivate TF
o Modify activity of TF
o Eg steroids
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