Regulation at the Transcriptional Level

Every cell in a multicellular organism contains the same genome, yet a muscle cell looks and behaves nothing like a neuron or a hepatocyte. The difference lies in which genes are expressed and how strongly. Regulation of gene expression at the transcriptional level is the most important and most economical point of control — it stops the cell from wasting energy making unwanted mRNA and protein. OCR A-Level Biology A specification module 6.1.1(b)(i) requires you to understand how transcription factors, chromatin remodelling and histone modification regulate eukaryotic gene expression.

Key Definitions:

• Gene expression — the process by which information in a gene is used to make a functional product (usually a protein).
• Transcription factor — a protein that binds to specific DNA sequences to regulate the rate of transcription.
• Promoter — the region of DNA upstream of a gene to which RNA polymerase and general transcription factors bind.
• Enhancer — a distant regulatory sequence that increases transcription when bound by specific activators.
• Chromatin — DNA wound around histone proteins in eukaryotic nuclei.
• Histone modification — post-translational chemical changes to histones (e.g. acetylation, methylation).
• Epigenetics — heritable changes in gene expression that do not involve changes in DNA base sequence.

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Levels of Control

Gene expression can be regulated at several levels, but transcriptional control is usually the first and most decisive.

flowchart TB
    A[Transcriptional control: when and how often a gene is transcribed]
    A --> B[Post-transcriptional: RNA splicing, editing, stability]
    B --> C[Translational: rate of ribosome binding and initiation]
    C --> D[Post-translational: protein folding, modification, degradation]

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Transcription Factors

Eukaryotic transcription cannot start without transcription factors (TFs). These proteins have one domain that recognises and binds a specific DNA sequence, and another that interacts with other proteins or with RNA polymerase itself.

There are two broad categories:

• General transcription factors (GTFs) — needed at every protein-coding gene. They assemble with RNA polymerase II on the promoter to form the "pre-initiation complex" at the TATA box (~25 bp upstream of the start site). Examples include TFIID, TFIIA, TFIIB.
• Specific transcription factors — bind enhancer or silencer sequences unique to particular genes. They may activate transcription (activators) or repress it (repressors).

How activators increase transcription

1. An activator protein binds an enhancer sequence, sometimes thousands of base pairs from the gene it controls.
2. DNA loops so that the enhancer-bound activator contacts the pre-initiation complex at the promoter.
3. The activator recruits mediator proteins, histone acetyltransferases (HATs) and other chromatin modifiers.
4. The local chromatin opens up, the polymerase is stabilised and transcription begins.

Example: oestrogen receptor

Oestrogen diffuses into a target cell and binds its nuclear oestrogen receptor (OR). The hormone-receptor complex is now a transcription factor: it enters the nucleus, binds to oestrogen response elements (EREs) in enhancers of target genes, and activates their transcription. This is how lipid-soluble hormones directly alter gene expression.

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Chromatin Remodelling

In eukaryotes, DNA is wound around histone octamers (2 of each of H2A, H2B, H3, H4) to form nucleosomes, which are further folded into 30 nm fibres and higher-order structures. This is called chromatin. Tightly packed chromatin (heterochromatin) is inaccessible to transcription machinery; loose, open chromatin (euchromatin) is accessible.

Chromatin-remodelling complexes are ATP-dependent machines that slide, eject or restructure nucleosomes so that the promoter becomes available for RNA polymerase and TFs. Without remodelling, transcription cannot begin — the DNA is literally hidden inside the nucleosome.

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Histone Modifications