Lecture notes from Imperial College London, Medical Biosciences BSc, 2nd year, genetics and genomics (GEN) module.
How is genomic DNA expressed, and how is it that different cell types with the same genome receive different instructions? In these notes, I delve deeper into transcription, and how...
Anatomy of a gene & gene expression
- gene expression = gene info used to synthesise a functional gene product (protein/ functional RNA)
- protein-coding gene:
sproximal)
regulatory regian
- stages of transcription: initiation - elongation - termination
- basal transcription machinery assembles at promoter
- transcription start site (TSS) core
- TATA box
promoter
RNA pol II + 5 transcription factors - UASs, enhancers, URSs, silencers...
(TFIIB, TFIID, TFIIE, TFIIF, TFIIH)
binds TATA box first + comprises TATA-binding protein (TBP) &
TBP-associated factors (TAFs)
=> initiation complex factors (= the others) bind TFIID
- mRNA processing: 5’-capping, splicing (intron removal), 3’-polyadenylation (poly A tail)
- transcription factor = protein binding at or close to the core promoter => modulate transcription
- DNA helicase = subunit of TFIIH using E from hydrolysis of ATP to open up the DNA double helix
- transcriptome = all mRNA molecules produced
- quantitative PCR (qPCR): quantity (relative abundance) a specific transcript sequence (w/ cDNA)
- gene expression microarrays: detect & quantify transcripts >1,000 genes (w/ fluorescent probes)
- RNA-Seq: uses next gen sequencing to tell which genes are expressed w/ which expression levels
by comparing sequenced fragments to a reference genome
Chromatin environment & gene expression
, - differences in expression of the ~200 cell types are maintained by epigenetic mechanisms
- DNA methylation of the 5th carbon of the cytosine ring => 5-methylcytosine
=> distort double helix
=> inhibits transcription/ silence gene if at promoter sunmethylated (pGislands in
promote
=> ~30,000 CpG islands (CGIs) in genome
(greater frequency of CpG dinucleotides)
=> many at gene promoters
- 1.5% DNA is 5-methylcytosine
-> silenced
-
- epigenetic inheritance can cause disease
=> genomic imprinting: DNA methylation ensures 1 parental allele is expressed and 1 silenced
=> ex: Prader-Willi Syndrome: silencing of maternal allele by imprinting AND deletion of
paternal allele in region of chr 15 with gene SNRPN
=> feeding problems: hyperphagia, insatiable appetite... + delayed motor skills
=> ex: Angelman Syndrome: silencing of paternal allele by imprinting AND deletion of maternal
allele in region of chr 15 with gene UBE3A
=> nervous system disorder: disabilities, seizures...
- histone tail modifications influence activity status of chromatin (euchromatin/ heterochromatin)
=> acetylation of histone H3 lysine 27: gene expression // tri-methylation: gene silencing
=> tri-methylation of histone H3 lysine 4: gene expression
=> di/ tri-methylation of histone H3 lysine 9: gene silencing
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