Regulation of gene expression
Introduzido| English | Significado |
|---|---|
| transcription factor/trænˈskrɪpʃn ˈfæktə/ | A protein that binds specific DNA sequences or interacts with transcription machinery to regulate gene expression. |
| enhancer | enhancer |
| chromatin | chromatin |
| methylation/ˌmeθɪˈleɪʃn/ | methylation |
| epigenetics/ˌepɪdʒɪˈnetɪks/ | The part of that access that is passed to daughter cells without changing the sequence. |
| nucleosome | nucleosome |
| epigenetic | epigenetic |
Same genes, different cells
- Almost every cell carries all of your ~20 000 genes. A neuron is a neuron because of which genes are on, when, and how much.
- That control layer is where evolution works fastest, and where much disease starts.
The control stack
- Transcription factors 转录因子 bind the promoter at the start of a gene, and enhancers 增强子 that can sit 100 kb away. DNA loops bring the enhancer to the promoter.
- Only about 1.5% of the genome codes protein; regulatory sequence is far larger.
How does an enhancer differ from a promoter?
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Enhancers loop to the promoter from up to about 100 kb away, in either orientation; the promoter sits at the start site.
Chromatin decides access
- Chromatin 染色质 state gates the DNA: histone marks open or close it, and CpG methylation 甲基化 keeps it shut. In a mature cell 70–80% of CpG sites are methylated.
- Epigenetics 表观遗传学 is the part of that access that is passed to daughter cells without changing the sequence.
Match each term to what it does.
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Sequence elements (promoter, enhancer), the proteins that read them (factors) and the marks that gate access (methylation) work together.
Why factors work in teams
- A factor reads about 6–8 bases. A random 6-mer turns up every $4^{6} = 4096$ bp, about 800 000 times on each strand of the 3.2 Gb genome: far too often to mean anything.
- Several factors binding side by side multiply the odds against a chance match, like a longer password. Enhancers are team logic gates.
Why can a single 6-base motif not regulate genes cleanly?
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4⁶ = 4096, so a 6-mer hits about every 4 kb. Several factors cooperating is what buys specificity, like a long password.
A factor reads 8 bases. About how many chance matches are there on one strand of a 3.2 Gb genome, in thousands?
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4⁸ = 65 536, and 3.2 × 10⁹ / 65 536 ≈ 48 800, about 49 thousand: two more bases cut the matches 16-fold, but still far too many alone.
Packing two metres
- The 2.2 m of DNA wraps around nucleosomes 核小体 (about 200 bp each), about 7-fold shorter, then folds into a ~30 nm fibre, about 40-fold.
- Loops and further folding bring a mitotic chromosome near $10^{4}$-fold. Packed regions are hard for factors to reach.
Put the packing stages in order, from least to most compact.
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About 7-fold, then about 40-fold, then near 10⁴-fold overall in a mitotic chromosome.
Worked example: drinking milk as an adult
- In most people the lactase gene (LCT) switches off after weaning. Many northern Europeans carry one base change about 14 kb upstream, inside an intron of a neighbouring gene.
- That base creates a stronger enhancer, so LCT stays on and adults digest milk. No protein changed, yet the trait spread across a continent.
Lactase persistence is caused by a change in the lactase enzyme's amino acids.
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The change is one regulatory base about 14 kb upstream that strengthens an enhancer; the enzyme itself is unchanged.
Worked example: twins who differ
- (Fictional) identical twins share a disease gene, but one is much sicker. In that twin, the gene's promoter is methylated; in the other it is not.
- Same letters, different access: an epigenetic 表观遗传的 modifier of severity. This is why methylation tests sit beside sequencers in the diagnostic lab.
Why can identical twins have different severity of the same genetic disease?
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Epigenetic marks pass through cell divisions yet can be reset; they are an access layer on top of the same letters.
Three common slips
- "Epigenetic means permanent." Marks pass through divisions but can be reset.
- "An enhancer is just a promoter." Enhancers work at a distance and in either orientation; the promoter sits at the start site.
- "Genes are ON or OFF." Expression is graded, and set by tissue and time.
Once a promoter is methylated, it can never be switched back on.
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Methylation passes through divisions but can be removed or reprogrammed, as happens in early embryos and with some drugs.
Recap
- ~20 000 genes, ~1.5% coding; enhancers loop to promoters and act as team switches.
- Methylation (70–80% of CpG) and histone marks gate access and pass to daughter cells.
- One regulatory base can change a trait without changing a protein.