10.8: Co-activators and Co-repressors

Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into co-activators or co-repressors based on their function.

An individual co-regulator can function either as a co-activator or a co-repressor, depending on its role in its associated complex. For example, the transcriptional co-repressor G9a participates in the activation of gene expression for a steroid hormone receptor along with other co-activators, such as GRIP1 and CARM1. Distinct domains of the protein perform these varied functions. In addition to the role in the complex, these regulators have enzymatic activities that can help regulate gene expression through the remodeling of the chromatin structure.

Histone acetyltransferases and histone demethylases function as co-activators; however, they first need to be localized to the regulatory site by a transcription activator to be able to perform these functions. Histone acetyltransferases can acetylate the lysine residues on the histone tails. Acetylation uncoils the chromatin and promotes gene expression. On the other hand, histone deacetylases and histone methyltransferases function as co-repressors. Both these modifications lead to the tightening up of chromatin structure and thereby lead to the prevention of gene expression.

Transcription is regulated by activators and repressors, proteins that bind to DNA. In eukaryotes, these regulatory proteins often need additional proteins, called co-regulators, to function properly.

These co-regulators bind to activator or repressor complexes; however, they do not recognize cis-regulatory sequences, as they cannot bind directly to DNA. 

A transcriptional regulator binds to a cis-regulatory sequence before the co-regulator associates; regulators and co-regulators often cannot form stable complexes unless the regulator is bound to DNA. In certain cases, RNA molecules also serve as scaffolds to hold all the proteins in a complex together.

Some of these co-regulators are enzymes that can regulate gene expression, such as histone acetyltransferases and deacetylases.

Acetyltransferases are co-activators that transfer an acetyl group to the histone leading to the loosening up of the DNA and promoting transcription. Deacetylases are co-repressors that remove acetyl groups resulting in the tight packing of DNA around the histones and preventing transcription.

For example, the co-regulator SMRT associates with the thyroid hormone receptor at the positive hormone response element and acts as a co-repressor to inhibit basal transcription. When a hormone binds to the receptor, the SMRT dissociates, and a co-activator binds to activate transcription. 

However, when bound to the same receptor on a negative hormone response element, SMRT activates transcription in the absence of the hormone. Thereby acting as a co-activator.