Coactivator (genetics)

{{Short description|Class of proteins involved in regulation of transcription}}

thumb|457x457px|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.<ref name="Courey_2008">{{cite book | title = Mechanisms in transcriptional regulation | last = Courey | first = Albert J. | name-list-style = vanc | date = 2008 | publisher = Blackwell | isbn = 978-1-4051-0370-1 | location = Malden, MA | oclc = 173367793 }}</ref> The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer.<ref name="Scitable_TF">{{cite web | url = https://www.nature.com/scitable/definition/transcription-factor-167 | title = General transcription factor / transcription factor | work = Learn Science at Scitable | access-date = 2017-11-29 }}</ref><ref name="Pennacchio_2013">{{cite journal | vauthors = Pennacchio LA, Bickmore W, Dean A, Nobrega MA, Bejerano G | title = Enhancers: five essential questions | journal = Nature Reviews Genetics | volume = 14 | issue = 4 | pages = 288–95 | date = April 2013 | pmid = 23503198 | pmc = 4445073 | doi = 10.1038/nrg3458 }}</ref> Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression.<ref name="Pennacchio_2013" /><ref name="Brown_2000">{{cite journal | vauthors = Brown CE, Lechner T, Howe L, Workman JL | title = The many HATs of transcription coactivators | journal = Trends in Biochemical Sciences | volume = 25 | issue = 1 | pages = 15–9 | date = January 2000 | pmid = 10637607 | doi = 10.1016/S0968-0004(99)01516-9 }}</ref><ref name="Kumar_2008">{{cite book | title = NR coregulators and human diseases | last1 = Kumar | first1 = Rakesh | last2 = O'Malley | first2 = Bert W. | name-list-style = vanc | publisher = World Scientific | year = 2008 | isbn = 978-981-270-536-5 | location=Hackensack, N.J. | oclc = 261137374 }}</ref> The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.<ref name="Scitable_TF"/>

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.<ref name="Courey_2008"/><ref name="Brown_2000"/>

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.<ref name="Courey_2008"/><ref name="Brown_2000"/> In eukaryotes, coactivators are usually proteins that are localized in the nucleus.<ref name="Courey_2008"/><ref name="Vosnakis_2017">{{cite journal | vauthors = Vosnakis N, Koch M, Scheer E, Kessler P, Mély Y, Didier P, Tora L | title = Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription | journal = The EMBO Journal | volume = 36 | issue = 18 | pages = 2710–2725 | date = September 2017 | pmid = 28724529 | doi = 10.15252/embj.201696035 | pmc=5599802}}</ref>

== Mechanism ==

thumb|400px|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.<ref name="Scitable_TF"/><ref name="Spiegelman_2004"/><ref name="Scholes_2016">{{cite journal | vauthors = Scholes NS, Weinzierl RO | title = Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions | journal = PLOS Computational Biology | volume = 12 | issue = 5 | article-number = e1004935 | date = May 2016 | pmid = 27175900 | doi = 10.1371/journal.pcbi.1004935 | pmc=4866707| bibcode = 2016PLSCB..12E4935S | doi-access = free }}</ref> 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.<ref name="Thomas_2006">{{cite journal | vauthors = Thomas MC, Chiang CM | title = The general transcription machinery and general cofactors | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 41 | issue = 3 | pages = 105–78 | date = May 2006 | pmid = 16858867 | doi = 10.1080/10409230600648736 | citeseerx = 10.1.1.376.5724 | s2cid = 13073440 }}</ref>

=== 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.<ref>{{cite journal|last=Decher|first=Gero|date=1997-08-29|title=Fuzzy Nanoassemblies: Toward Layered Polymeric Multicomposites|journal=Science|language=en|volume=277|issue=5330|pages=1232–1237|doi=10.1126/science.277.5330.1232|issn=0036-8075}}</ref> 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.<ref name="Brown_2000"/><ref name="Spiegelman_2004">{{cite journal | vauthors = Spiegelman BM, Heinrich R | title = Biological control through regulated transcriptional coactivators | journal = Cell | volume = 119 | issue = 2 | pages = 157–67 | date = October 2004 | pmid = 15479634 | doi = 10.1016/j.cell.2004.09.037 | s2cid = 14668705 | doi-access = free }}</ref><ref name="Hermanson_2002">{{cite journal | vauthors = Hermanson O, Glass CK, Rosenfeld MG | title = Nuclear receptor coregulators: multiple modes of modification | journal = Trends in Endocrinology and Metabolism | volume = 13 | issue = 2 | pages = 55–60 | year = 2002 | pmid = 11854019 | doi = 10.1016/s1043-2760(01)00527-6 | s2cid = 38649132 }}</ref> 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.<ref name="Spiegelman_2004"/><ref name="Hermanson_2002" /> 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).<ref name="Brown_2000" /><ref name="Hermanson_2002" /> Acetylation by HAT complexes may also help keep chromatin open throughout the process of elongation, increasing the speed of transcription.<ref name="Brown_2000" />

thumb|400px|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.<ref name="Van Damme_2001">{{cite journal | vauthors = Van Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T | title = NatF contributes to an evolutionary shift in protein N-terminal acetylation and is important for normal chromosome segregation | journal = PLOS Genetics | volume = 7 | issue = 7 | article-number = e1002169 | date = July 2011 | pmid = 21750686 | pmc = 3131286 | doi = 10.1371/journal.pgen.1002169 | doi-access = free }}</ref> Acetylation is crucial for synthesis, stability, function, regulation and localization of proteins and RNA transcripts.<ref name="Hermanson_2002" /><ref name="Van Damme_2001" />

HATs function similarly to N-terminal acetyltransferases (NATs) but their acetylation is reversible unlike in NATs.<ref>{{cite journal | vauthors = Starheim KK, Gevaert K, Arnesen T | title = Protein N-terminal acetyltransferases: when the start matters | journal = Trends in Biochemical Sciences | volume = 37 | issue = 4 | pages = 152–61 | date = April 2012 | pmid = 22405572 | doi = 10.1016/j.tibs.2012.02.003 }}</ref> HAT mediated histone acetylation is reversed using histone deacetylase (HDAC), which catalyzes the hydrolysis of lysine residues, removing the acetyl group from the histones.<ref name="Brown_2000" /><ref name="Spiegelman_2004"/><ref name="Hermanson_2002" /> 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.<ref name="Brown_2000" /><ref name="Spiegelman_2004"/>

Examples of coactivators that display HAT activity include CARM1, CBP and EP300.<ref name="Lonard_2012">{{cite journal | vauthors = Lonard DM, O'Malley BW | title = Nuclear receptor coregulators: modulators of pathology and therapeutic targets | journal = Nature Reviews. Endocrinology | volume = 8 | issue = 10 | pages = 598–604 | date = October 2012 | pmid = 22733267 | doi = 10.1038/nrendo.2012.100 | pmc=3564250}}</ref><ref name="Hsia_2010">{{cite journal | vauthors = Hsia EY, Goodson ML, Zou JX, Privalsky ML, Chen HW | title = Nuclear receptor coregulators as a new paradigm for therapeutic targeting | journal = Advanced Drug Delivery Reviews | volume = 62 | issue = 13 | pages = 1227–37 | date = October 2010 | pmid = 20933027 | doi = 10.1016/j.addr.2010.09.016 | pmc=5004779}}</ref>

=== Corepression ===

Many coactivators also function as corepressors under certain circumstances.<ref name="Kumar_2008"/><ref name="Thomas_2006"/> 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).<ref name="Thomas_2006"/>

== Significance ==

=== Biological significance ===

Transcriptional regulation is one of the most common ways for an organism to alter gene expression.<ref name="Scitable_Enhancer">{{cite web | url = https://www.nature.com/scitable/definition/enhancer-163 | title = Enhancer | work = Learn Science at Scitable | access-date=2017-11-29 }}</ref> The use of activation and coactivation allows for greater control over when, where and how much of a protein is produced.<ref name="Courey_2008"/><ref name="Spiegelman_2004"/><ref name="Scitable_Enhancer" /> 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.<ref name="Courey_2008" /><ref name="Spiegelman_2004" />

=== 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.<ref>{{cite book | title = Molecular Cell Biology | date = 2000 | publisher = W.H. Freeman | first1 = Arnold | last1 = Berk | first2 = S. Lawrence | last2 = Zipursky | first3 = Paul T. | last3 = Matsudaira | first4 = David | last4 = Baltimore | first5 = James | last5 = Darnell | editor-first1 = Harvey F. | editor-last1 = Lodish | name-list-style = vanc | isbn = 978-0-7167-3136-8 | edition = 4th | location = New York | oclc = 41266312 | url-access = registration | url = https://archive.org/details/molecularcellbio00lodi }}</ref><ref name="Kumar_2008"/> 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.<ref name="Kumar_2008" /> 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.<ref name="Lonard_2012" /><ref>{{cite journal | last1 = Becnel | first1 = LB | last2 = Darlington | first2 = YF | last3 = Orechsner | first3 = S | last4 = Easton-Marks | first4 = J | last5 = Watkins | first5 = CA | last6 = McOwiti | first6 = A | last7 = Kankanamge | first7 = WH | last8 = Dehart | first8 = M | last9 = Silva | first9 = CM | name-list-style = vanc | title = CBP | journal = NURSA Molecules | doi = 10.1621/8egsudafco | doi-broken-date = 13 November 2025 }}</ref>

=== 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.<ref name="Kumar_2008" /><ref>{{cite web | url = https://courses.washington.edu/conj/bess/nuclear/nuclear.htm|title=Nuclear Receptors | website=courses.washington.edu | access-date = 2017-11-29 }}</ref> 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.<ref name="Hsia_2010" /><ref>{{cite journal | vauthors = Tien JC, Xu J | title = Steroid receptor coactivator-3 as a potential molecular target for cancer therapy | journal = Expert Opinion on Therapeutic Targets | volume = 16 | issue = 11 | pages = 1085–96 | date = November 2012 | pmid = 22924430 | doi = 10.1517/14728222.2012.718330 | pmc=3640986}}</ref>

Because transcription factors control many different biological processes, they are ideal targets for drug therapy.<ref name="Lonard_2012" /><ref>{{cite journal | vauthors = Sladek FM | title = Nuclear receptors as drug targets: new developments in coregulators, orphan receptors and major therapeutic areas | journal = Expert Opinion on Therapeutic Targets | volume = 7 | issue = 5 | pages = 679–84 | date = October 2003 | pmid = 14498828 | doi = 10.1517/14728222.7.5.679 | s2cid = 16891519 }}</ref> 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.<ref name="Lonard_2012" />

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.<ref name="Lonard_2012" /><ref name="Hsia_2010" />

== Known coactivators ==

To date there are more than 300 known coregulators.<ref name="Hsia_2010" /> Some examples of these coactivators include:<ref>{{cite web|url=https://nursa.org/nursa/molecules/index.jsf|title=NURSA - Molecules|website=nursa.org|language=en|access-date=2017-11-30}}</ref> * ARA54 targets androgen receptors * ATXN7L3 targets several members of the nuclear receptor superfamily * BCL3 targets 9-cis retinoic acid receptor (RXR) * CBP targets many transcription factors * CDC25B targets steroid receptors * COPS5 targets several nuclear receptors * DDC targets androgen receptors * EP300 targets many transcription factors * KAT5 targets many nuclear receptors * KDM1A targets androgen receptors * Steroid receptor coactivator (SRC) family ** NCOA1 targets several members of the nuclear receptor superfamily ** NCOA2 targets several members of the nuclear receptor superfamily ** NCOA3 targets several nuclear receptors and transcription factors * YAP targets transcription factors * WWTR1 targets transcription factors

== References == {{Reflist}}

== External links ==

* [http://www.nursa.org/ Nuclear Receptor Signalling Atlas] (NIH-funded research consortium and database; includes open-access PubMed-indexed journal, ''Nuclear Receptor Signaling'') * [http://cbrc.kaust.edu.sa/tcof/ TcoF - Dragon database of transcription co-factors and transcription factor interacting proteins]

Category:Gene expression Category:Molecular genetics Category:Proteins Category:Transcription coregulators