Gene regulation is the selective process that controls which proteins are made, when they are made, and how much of them are produced. Cells do not express all of their approximately 20,000 genes at the same time. The blueprint for all proteins is stored in DNA, and the first step is transcription, where a segment of DNA is copied into a messenger RNA (mRNA) molecule. Cells utilize molecular “switches” to precisely govern this copying process, ensuring only the necessary genetic instructions are executed. This ability to turn genes “on” and “off” allows organisms to develop complex structures and adapt to environmental changes.
Defining Transcriptional Repression
Transcriptional repression actively prevents cellular machinery from copying a specific gene into RNA. In complex organisms, a corepressor is a protein that functions as an indirect silencer of gene expression. A corepressor cannot bind directly to the DNA sequence of the gene it is silencing. Instead, it must be recruited by a separate protein known as a sequence-specific DNA-binding repressor.
This forms an obligatory partnership where the repressor protein locates and attaches to a specific regulatory segment of the DNA. Once docked, the repressor acts as a landing pad to recruit the corepressor complex. The corepressor then executes the work of silencing the gene’s activity, ensuring repression is targeted only to the genes marked by the repressor.
The corepressor acts as a molecular bridge, connecting the DNA repressor to the machinery that physically shuts down transcription. This partnership ultimately blocks the cell’s RNA-making enzyme, RNA polymerase, from accessing the gene and initiating the transcription process. Well-studied examples include Nuclear Receptor Corepressor 1 (NCoR1) and Silencing Mediator for Retinoid and Thyroid-hormone Receptor (SMRT).
Molecular Function and Mechanism
A corepressor achieves gene silencing by altering the physical structure of chromatin. Chromatin is the complex of DNA tightly wound around proteins called histones, forming structures called nucleosomes. This packaging determines whether a gene is accessible for transcription.
The corepressor recruits specific enzymes that chemically modify the histones, making the DNA wrapping tighter. The most common enzymes recruited are Histone Deacetylases (HDACs). HDACs remove acetyl groups from the histone tails, chemical tags that normally keep the chromatin structure looser.
The removal of these acetyl groups, known as deacetylation, causes the positively charged histones to bind more tightly to the negatively charged DNA. This results in chromatin compaction, physically compressing the DNA into a dense, inaccessible state. When the DNA is packed tightly, the transcription machinery, including RNA polymerase, is physically blocked from reaching the gene’s sequence.
Corepressors vs. Coactivators
Cellular control over gene expression is a dynamic balance between repression and activation, meaning corepressors operate in opposition to coactivators. Coactivators are proteins that, like corepressors, do not bind DNA directly but are recruited by sequence-specific activator proteins. While corepressors turn genes off, coactivators function to turn genes on.
The difference between them lies in their effect on chromatin structure. Corepressors recruit HDACs to promote the condensed, “off” state of chromatin. Coactivators, conversely, recruit enzymes that chemically loosen the chromatin structure, facilitating the “on” state. These enzymes are often Histone Acetyltransferases (HATs), which add acetyl groups to histone tails.
The addition of acetyl groups by HATs neutralizes the positive charge on the histones, weakening their grip on the DNA. This causes the chromatin to decondense, creating an open structure. This open chromatin structure makes the underlying gene sequence accessible to the transcriptional machinery.
Corepressors in Health and Disease
Corepressors are central regulators of the gene “off switch” and are involved in fundamental biological processes like development and metabolism. Corepressor complexes are necessary for proper system development and help regulate genes involved in energy metabolism.
Disrupted corepressor function leads to dysregulated gene expression and various diseases, including cancer. Errors or mutations in corepressor genes are frequently implicated in cancer development. For example, mutations in genes like BCOR and BCORL1 are recurrently found in acute myeloid leukemia (AML).
In cancer, corepressors may be dysfunctional, allowing cell growth-promoting genes to be inappropriately expressed. Conversely, they can be aberrantly recruited to silence tumor suppressor genes. Because corepressors depend on HDAC activity, these enzymes have become a target for drug development aimed at restoring proper gene expression control.