Gene Expression & Epigenetics
Every cell in an organism carries the same DNA, yet a neuron and a skin cell are very different. The difference lies in which genes are switched on in each cell. This is gene expression: a gene is said to be expressed when it is turned on and its product is being made.
HOW GENE EXPRESSION IS CONTROLLED
Immediately upstream of a gene sits its promoter - a stretch of DNA that is not transcribed itself, but is where RNA polymerase binds. Transcription factors are proteins (made by other genes) that position the polymerase and set the rate of transcription:
- Activators - transcription factors that bind DNA to switch a gene on or speed transcription up.
- Repressors - transcription factors that bind DNA to slow or stop transcription.
Cells can regulate expression at four levels:
- The rate of transcription - the most common control point.
- The processing of immature mRNA - whether and how introns are removed.
- The stability of the mRNA - a transcript can be degraded before it is used.
- The rate of translation at the ribosome.
The environment also influences these controls: extreme temperatures can switch genes on or off, chemicals and drugs can induce or repress genes, the same genes are expressed differently in each sex, and the products of other genes - hormones and transcription factors - feed back on expression.
GENOTYPE AND PHENOTYPE
| Genotype | Phenotype | |
|---|---|---|
| What it is | genetic makeup - the alleles carried | observable characteristics |
| Determined by | DNA sequence only | expressed genes and environment |
| Measured by | DNA sequencing | observation and measurement |
| Inherited? | yes | no - only the genes are |
| Which genes count | all - expressed and suppressed | expressed genes only |
DIFFERENTIATION AND STEM CELLS
Control of gene expression drives cellular differentiation: as tissues grow and develop, different genes are activated in different cells, making the cells specialised and distinct. The whole of embryogenesis - development from embryo to birth - is coordinated in this way.
- Pluripotent stem cells - can become any cell type, given the right signal (embryonic stem cells).
- Multipotent stem cells - can only become a family of closely related cell types (for example haematopoietic adult stem cells, which form the blood cells).
EPIGENETICS
Epigenetic changes alter gene expression without changing the DNA sequence - the phenotype changes while the genotype stays the same. There are two main mechanisms:
- DNA methylation - a methyl (-CH₃) group is added to the DNA, usually on a cytosine base. Methylation tightens the coiling of DNA around its histones, blocking RNA polymerase; the gene is silenced.
- Histone modification - acetyl groups added to the histone proteins loosen the coiling, making the DNA more accessible; expression usually increases.
Methylation of a gene switches it off without altering the underlying DNA sequence.
Methyl tags (filled circles) tighten DNA around histones; acetyl tags (open circles) loosen the coiling for transcription.
| DNA methylation | Histone acetylation | |
|---|---|---|
| Tag added | methyl group, usually on cytosine | acetyl group on the histone |
| Effect on coiling | tighter | looser |
| Effect on expression | usually silenced | usually increased |
Methylation patterns are not fixed. They change over a lifetime, differ between cell types of the same organism, and shift with the environment - stress, diet, and chemicals such as cigarette smoke. This is why identical twins (and clones) become less identical with age, and some epigenetic marks may even be heritable.
EPIGENETICS AND CANCER
Healthy cell division is controlled by cell-cycle checkpoints; cancer cells escape those checkpoints and divide uncontrollably. Two classes of gene are involved: proto-oncogenes (normal growth genes that mutation can convert into cancer-driving oncogenes) and tumour suppressor genes, whose role is to stop or slow division.
The key mechanism to understand: in healthy cells the control regions of tumour suppressor genes are unmethylated. If methylation increases there, the DNA coils more tightly, transcription cannot occur, the suppressor protein is never made - and cell division continues unchecked.
Changed methylation is also linked to Alzheimer's disease, multiple sclerosis and Fragile X syndrome - caused by changes to the FMR1 gene, the most common single-gene cause of autism worldwide, and generally more severe in males.
Because epigenetic changes can be as informative as mutations, scientists have adapted PCR, DNA sequencing, mass spectroscopy and ELISA into tools that map where, and how heavily, a person's genes are methylated - an emerging diagnostic tool for detecting cancer.