Regulation of Gene Expression in Eukaryotes

DNA exists as chromosomes within the nucleus of a cell and carries important genetic instructions. The segment of a DNA molecule that codes for a distinct protein is known as a gene.

Gene transcribes to an mRNA
mRNA translates to a specific polypeptide chain
Polypeptide chain folds/modifies into a functional protein

The genetic code hidden within the DNA segment is phenotypically expressed with the formation of the specific protein; the entire process, when a gene in DNA is ‘turned on’ to make the protein, is known as gene expression.

The process of controlling gene expression is known as gene regulation. Even after containing the same DNA, different cells in a multicellular organism express different sets of genes; the set of genes expressed in a cell determines its unique properties. In eukaryotes, gene regulation can occur at any step of gene expression.

Mechanisms of Gene Expression Regulation in Eukaryotes

Eukaryotic gene expression involves many steps, and almost all of them can be regulated and it is not uncommon for a gene to be regulated at multiple steps. The main control point for most genes is transcription, but later stages of regulation often refine the pattern of gene expression. Some most important steps that are regulated might include-

Chromatin accessibility: Chromatin structures (consisting of DNA and the organising proteins) can be regulated. The relaxed chromatin model makes a gene available for transcription.
Transcription: The key regulatory point, where sets of transcription factors bind to DNA sequences to promote or repress the transcription into RNA.
RNA processing: After transcription, 5’-capping, 3'-polyadenylation, and splicing of the RNA molecule and its exit from the nucleus can be regulated. The same pre-mRNA can produce different mRNAs by alternative splicing.
Translation: Various regulators and miRNAs can increase or inhibit the translation of an mRNA.
Protein activity: Proteins can undergo a variety of modifications that can be regulated. This might affect the activity of the protein.

Regulation of Chromatin Accessibility

The binding of the DNA around the supporting proteins can affect the availability of a gene to undergo transcription. Chromatin remodelling indirectly controls the transcription of a gene. The presence of nucleosomes (histone complexes and DNA) is disrupted for the eukaryotic gene regulation processes.

Acetylation and Deacetylation: It occurs on the lysine residues of the histone molecules. This reduces the positive charge and decreases the binding affinity of histone to the negatively charged DNA. Thus, acetylation helps to relax the chromatin model and allows the transcription factors to bind readily to the DNA segments. Deacetylation has the reverse effects.
Methylation and Demethylation: Occur at cytosine residues, usually in CpG dinucleotides of the DNA that resist transcription. Demethylation has the reverse effect, associated with an increased transcription rate.

Regulation of Transcription

Transcription is the key control point of gene expression. It is the process where the DNA sequence of a gene is transcribed (copied) into an RNA molecule. Eukaryotes contain numerous transcription factors (TF), which are proteins that regulate the transcription of genes.

In eukaryotes, RNA polymerase can attach to the promoter only with the help of basal (general) transcription factors. The specialised class of transcription factors control the expression of specific, individual genes that help or resist the RNA Polymerase from binding.

Activators/Enhancers: Transcription factors that help the basal transcription factors and/or RNA polymerase bind to the promoter, thus activating the process of transcription.
Repressors: Transcription factors that block or reduce RNA polymerase binding or activity, either at the promoter or by binding to silencer elements.
Binding sites: Enhancer and silencer binding sites may be located far upstream, downstream, or even within introns.

Regulation of RNA Processing

In eukaryotes, the nascent transcribed RNA is not yet considered a messenger RNA (mRNA) and is known as the pre-mRNA. The pre-mRNA undergoes modifications like 5’-capping, 3'-polyadenylation, and splicing, which can potentially be regulated to produce different products.

Alternative Splicing

Most pre-mRNA molecules have sections that are removed from the molecule, called introns, and sections that are linked together to make the final mRNA, called exons. This process is called splicing. During alternative splicing, different portions of an mRNA can be selected for use as exons, thus resulting in two different mRNAs from a single pre-mRNA.

Regulatory proteins typically control this process. Different types of cells express different regulatory proteins, leading to different exon combinations and the production of different proteins.

Regulation of Translation

In order to initiate translation, the ribosome and an RNA-protein complex must assemble on the mRNA. Many ‘helper’ proteins control the correct positioning of the ribosome. Translation can be regulated on the basis of the availability of the ‘helper’ proteins.

Regulation of Proteins

In eukaryotes, regulatory mechanisms also act on proteins that are already produced. In these cases, the protein is edited through the removal of amino acids or the addition of a chemical, etc., that can lead to a change in its activity.

Phosphorylation: A phosphate group is attached to a protein. The effect varies from protein to protein: some are activated, while others are deactivated, and others yet simply change their behaviour (interact with different compounds).
Ubiquitination: Addition of a chemical marker called ubiquitin to a protein. Ubiquitin-tagged proteins are directed to the proteasome for degradation into peptides. It is an important way of controlling the persistence of a protein in the cell.

Frequently Asked Questions (FAQs)

Q1. How do cells decide which genes to turn on?

A. Different sets of genes are expressed in different types of cells; even the same type of two different cells also exhibit different gene expression patterns depending on their intrinsic (any DNA damage, ATP content, etc.) and extrinsic (mechanical signals from the extracellular matrix, chemical signals from other cells, etc.) information. Cells have molecular pathways that transduce this information as a signal that finally makes a change in gene expression.

Q2. What are the three stages in gene expression in eukaryotes?

A. Transcription (DNA → RNA), RNA processing (mRNA maturation), and translation (mRNA → protein) are the three stages in gene expression.