Coactivator (genetics)

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The activator, thyroid hormone receptor (TR), is bound to a corepressor preventing transcription of the target gene. The binding of a ligand hormone causes the corepressor to dissociate and a coactivator is recruited. The activator bound coactivator recruits RNA polymerase and other transcription machinery that then begins transcribing the target gene. Type ii nuclear receptor action.png
The activator, thyroid hormone receptor (TR), is bound to a corepressor preventing transcription of the target gene. The binding of a ligand hormone causes the corepressor to dissociate and a coactivator is recruited. The activator bound coactivator recruits RNA polymerase and other transcription machinery that then begins transcribing the target gene.

A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. [1] The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. [2] [3] Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. [3] [4] [5] The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage. [2]

Contents

Some coactivators also have histone acetyltransferase (HAT) activity. HATs form large multiprotein complexes that weaken the association of histones to DNA by acetylating the N-terminal histone tail. This provides more space for the transcription machinery to bind to the promoter, therefore increasing gene expression. [1] [4]

Activators are found in all living organisms, but coactivator proteins are typically only found in eukaryotes because they are more complex and require a more intricate mechanism for gene regulation. [1] [4] In eukaryotes, coactivators are usually proteins that are localized in the nucleus. [1] [6]

Mechanism

Histone acetyltransferase (HAT) removes the acetyl group from acetyl-CoA and transfers it the N-terminal tail of chromatin histones. In the reverse reaction, histone deacetylase (HDAC) removes the acetyl group from the histone tails and binds it to coenzyme A to form acetyl-CoA. Histone acetylation and deacetylation.jpg
Histone acetyltransferase (HAT) removes the acetyl group from acetyl-CoA and transfers it the N-terminal tail of chromatin histones. In the reverse reaction, histone deacetylase (HDAC) removes the acetyl group from the histone tails and binds it to coenzyme A to form acetyl-CoA.

Some coactivators indirectly regulate gene expression by binding to an activator and inducing a conformational change that then allows the activator to bind to the DNA enhancer or promoter sequence. [2] [7] [8] Once the activator-coactivator complex binds to the enhancer, RNA polymerase II and other general transcription machinery are recruited to the DNA and transcription begins. [9]

Histone acetyltransferase

Nuclear DNA is normally wrapped tightly around histones, making it hard or impossible for the transcription machinery to access the DNA. This association is due primarily to the electrostatic attraction between the DNA and histones as the DNA phosphate backbone is negatively charged and histones are rich in lysine residues, which are positively charged. [10] The tight DNA-histone association prevents the transcription of DNA into RNA.

Many coactivators have histone acetyltransferase (HAT) activity meaning that they can acetylate specific lysine residues on the N-terminal tails of histones. [4] [7] [11] In this method, an activator binds to an enhancer site and recruits a HAT complex that then acetylates nucleosomal promoter-bound histones by neutralizing the positively charged lysine residues. [7] [11] This charge neutralization causes the histones to have a weaker bond to the negatively charged DNA, which relaxes the chromatin structure, allowing other transcription factors or transcription machinery to bind to the promoter (transcription initiation). [4] [11] Acetylation by HAT complexes may also help keep chromatin open throughout the process of elongation, increasing the speed of transcription. [4]

N-terminal acetyltransferase (NAT) transfers the acetyl group from acetyl coenzyme A (Ac-CoA) to the N-terminal amino group of a polypeptide. Protein-acetylation-nterminal.svg
N-terminal acetyltransferase (NAT) transfers the acetyl group from acetyl coenzyme A (Ac-CoA) to the N-terminal amino group of a polypeptide.

Acetylation of the N-terminal histone tail is one of the most common protein modifications found in eukaryotes, with about 85% of all human proteins being acetylated. [12] Acetylation is crucial for synthesis, stability, function, regulation and localization of proteins and RNA transcripts. [11] [12]

HATs function similarly to N-terminal acetyltransferases (NATs) but their acetylation is reversible unlike in NATs. [13] HAT mediated histone acetylation is reversed using histone deacetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones. [4] [7] [11] This causes the chromatin to close back up from their relaxed state, making it difficult for the transcription machinery to bind to the promoter, thus repressing gene expression. [4] [7]

Examples of coactivators that display HAT activity include CARM1, CBP and EP300. [14] [15]

Corepression

Many coactivators also function as corepressors under certain circumstances. [5] [9] Cofactors such as TAF1 and BTAF1 can initiate transcription in the presence of an activator (act as a coactivator) and repress basal transcription in the absence of an activator (act as a corepressor). [9]

Significance

Biological significance

Transcriptional regulation is one of the most common ways for an organism to alter gene expression. [16] The use of activation and coactivation allows for greater control over when, where and how much of a protein is produced. [1] [7] [16] This enables each cell to be able to quickly respond to environmental or physiological changes and helps to mitigate any damage that may occur if it were otherwise unregulated. [1] [7]

Associated disorders

Mutations to coactivator genes leading to loss or gain of protein function have been linked to diseases and disorders such as birth defects, cancer (especially hormone dependent cancers), neurodevelopmental disorders and intellectual disability (ID), among many others. [17] [5] Dysregulation leading to the over- or under-expression of coactivators can detrimentally interact with many drugs (especially anti-hormone drugs) and has been implicated in cancer, fertility issues and neurodevelopmental and neuropsychiatric disorders. [5] For a specific example, dysregulation of CREB-binding protein (CBP)—which acts as a coactivator for numerous transcription factors within the central nervous system (CNS), reproductive system, thymus and kidneys—has been linked to Huntington's disease, leukaemia, Rubinstein-Taybi syndrome, neurodevelopmental disorders and deficits of the immune system, hematopoiesis and skeletal muscle function. [14] [18]

As drug targets

Coactivators are promising targets for drug therapies in the treatment of cancer, metabolic disorder, cardiovascular disease and type 2 diabetes, along with many other disorders. [5] [19] For example, the steroid receptor coactivator (SCR) NCOA3 is often overexpressed in breast cancer, so the development of an inhibitor molecule that targets this coactivator and decreases its expression could be used as a potential treatment for breast cancer. [15] [20]

Because transcription factors control many different biological processes, they are ideal targets for drug therapy. [14] [21] The coactivators that regulate them can be easily replaced with a synthetic ligand that allows for control over an increase or decrease in gene expression. [14]

Further technological advances will provide new insights into the function and regulation of coactivators at a whole-organism level and elucidate their role in human disease, which will hopefully provide better targets for future drug therapies. [14] [15]

Known coactivators

To date there are more than 300 known coregulators. [15] Some examples of these coactivators include: [22]

See also

Related Research Articles

<span class="mw-page-title-main">Transcription factor</span> Protein that regulates the rate of DNA transcription

In molecular biology, a transcription factor (TF) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired cells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone. There are 1500-1600 TFs in the human genome. Transcription factors are members of the proteome as well as regulome.

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">EP300</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene. It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.

p300-CBP coactivator family Protein family

The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins :

  1. p300
  2. CBP

In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that repress are known as corepressors. The mechanism of action of transcription coregulators is to modify chromatin structure and thereby make the associated DNA more or less accessible to transcription. In humans several dozen to several hundred coregulators are known, depending on the level of confidence with which the characterisation of a protein as a coregulator can be made. One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.

<span class="mw-page-title-main">PCAF</span> Protein-coding gene in the species Homo sapiens

P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.

<span class="mw-page-title-main">CREB-binding protein</span> Nuclear protein that binds to CREB

CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span>

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

<span class="mw-page-title-main">Nuclear receptor coactivator 1</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransferase activity. It is encoded by the gene NCOA1.

<span class="mw-page-title-main">Nuclear receptor coactivator 3</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).

<span class="mw-page-title-main">KAT2A</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase KAT2A is an enzyme that in humans is encoded by the KAT2A gene.

<span class="mw-page-title-main">KAT5</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene. It is also commonly identified as TIP60.

<span class="mw-page-title-main">NCOA6</span> Protein-coding gene in the species Homo sapiens

Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.

<span class="mw-page-title-main">KAT6A</span> Protein-coding gene in the species Homo sapiens

K(lysine) acetyltransferase 6A (KAT6A), is an enzyme that, in humans, is encoded by the KAT6A gene. This gene is located on human chromosome 8, band 8p11.21.

<span class="mw-page-title-main">TAF5L</span> Protein-coding gene in the species Homo sapiens

TAF5-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 5L is an enzyme that in humans is encoded by the TAF5L gene.

Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.

<span class="mw-page-title-main">KIX domain</span>

In biochemistry, the KIX domain (kinase-inducible domain (KID) interacting domain) or CREB binding domain is a protein domain of the eukaryotic transcriptional coactivators CBP and P300. It serves as a docking site for the formation of heterodimers between the coactivator and specific transcription factors. Structurally, the KIX domain is a globular domain consisting of three α-helices and two short 310-helices.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

References

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