Regulation of transcription and translation (A-level only) — AQA A-Level Biology

A transcriptional factor is a protein that controls whether a particular gene is transcribed. Many are held inactive in the cytoplasm until a signal arrives; once activated they pass through a nuclear pore into the nucleus and bind to a specific base sequence in the promoter region, the stretch of DNA lying just before the gene. The binding site of the factor is complementary in shape to that sequence, so each factor only affects its own target genes. A stimulatory factor helps RNA polymerase attach to the promoter, so transcription begins, mRNA is produced and the polypeptide is made. An inhibitory factor blocks the promoter, so RNA polymerase cannot bind and no mRNA is transcribed. The gene itself is unchanged in every case; only the amount of mRNA changes.

Oestrogen is a steroid hormone, so it is lipid-soluble and diffuses straight through the phospholipid bilayer of the cell-surface membrane rather than binding on the outside. Inside the cell it binds to a receptor site on an oestrogen receptor, which is part of a transcriptional factor held inactive in the cytoplasm. Binding changes the tertiary structure of the receptor, releasing an inhibitor molecule and activating the factor. The oestrogen-receptor complex then moves into the nucleus and binds to the promoter region of its target genes, where it stimulates RNA polymerase so that transcription begins. mRNA is produced, translated at ribosomes, and the resulting proteins drive processes such as cell division in breast tissue.

Epigenetic control determines which eukaryotic genes are transcribed, without altering the DNA base sequence. DNA wraps around histones to form chromatin. How tightly it winds dictates if transcription factors and RNA polymerase can access the promoter. Increased methylation of cytosine bases in the promoter inhibits transcription by preventing protein binding and condensing chromatin. Conversely, adding acetyl groups to histones reduces their positive charge, weakening their attraction to DNA's phosphate groups. This loosens chromatin, stimulating transcription. Environmental factors alter these tags. These epigenetic changes can be maintained during DNA replication and passed to daughter cells, explaining how environmental influences can be heritable.

Epigenetics is defined as heritable changes in gene function that occur without any change to the base sequence of DNA. The tags that carry these changes make up the epigenome, and it is the epigenome, not the genome, that responds to the environment: diet, smoking, stress and toxins can all alter it. Two changes inhibit transcription and both must be learned in the right direction. Increased methylation means methyl groups attach to cytosine bases in the promoter region; transcription factors can no longer bind there and the DNA coils more tightly, so the gene is not transcribed. Decreased acetylation means acetyl groups are removed from the histones by histone deacetylase; the histones become more positively charged, bind the negatively charged DNA more strongly, the chromatin condenses and RNA polymerase cannot reach the promoter.

Cancer arises when the epigenome is disrupted as well as when genes mutate. In many tumours the promoter region of a tumour suppressor gene becomes hypermethylated, so it is not transcribed; the protein that would normally slow the cell cycle or trigger apoptosis is not made, and damaged cells keep dividing. Oncogenes can be affected the other way: reduced methylation or increased acetylation of histones associated with the oncogene means it is transcribed more, so cell division is stimulated. Because no base has been altered, these changes are in principle reversible, which is what makes them attractive drug targets. Drugs that inhibit DNA methyltransferase reduce methylation of tumour suppressor genes so they are expressed again, while histone deacetylase inhibitors increase acetylation, loosening the chromatin and allowing transcription.

RNA interference silences a gene after its mRNA has already been made, so transcription is unaffected. Double-stranded RNA in the cytoplasm is cut by an enzyme, dicer, into short lengths of about 21 nucleotides called small interfering RNA, siRNA. One strand of each siRNA is taken up by a protein complex, RISC. The siRNA acts as a guide: its bases pair with complementary bases on any mRNA carrying that sequence. Once the complex is attached, the enzyme in it cuts the mRNA into fragments, which are then hydrolysed in the cytoplasm. The mRNA never reaches a ribosome, so no polypeptide is translated and the gene is effectively switched off. microRNA works in a similar way but pairs less precisely, so it can block translation of several different mRNA molecules rather than destroying one. RNAi occurs in eukaryotes and in some prokaryotes, and is used experimentally to test what a gene does.

Data interpretation here involves mRNA concentrations, promoter methylation, or monozygotic twin comparisons. Interpretation requires two steps. First, describe the pattern using figures with units and make requested comparisons. Second, explain the pattern using mechanisms like transcription factor binding, DNA methylation, histone acetylation, or RNA interference. Evaluating genetic versus environmental influences requires careful experimental design. While monozygotic twins share their alleles, phenotypic differences between them are largely attributed to environmental factors, though somatic mutations and epigenetic effects also contribute. Conversely, genetically different individuals raised in identical conditions highlight genetic influences.