Corepressor

{{Short description|Molecule that represses the expression of genes}} In genetics and molecular biology, a '''corepressor''' is a molecule that represses the expression of genes.<ref>{{Cite book|url=http://link.springer.com/10.1007/978-3-662-10595-5|title=Transcriptional Corepressors: Mediators of Eukaryotic Gene Repression|date=2001|publisher=Springer Berlin Heidelberg|isbn=978-3-642-08709-7|editor-last=Privalsky|editor-first=Martin L.|series=Current Topics in Microbiology and Immunology|volume=254|location=Berlin, Heidelberg|language=en|doi=10.1007/978-3-662-10595-5|s2cid=8922796 }}</ref> In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, but instead indirectly regulates gene expression by binding to repressors.

A corepressor downregulates (or represses) the expression of genes by binding to and activating a repressor transcription factor. The repressor in turn binds to a gene's operator sequence (segment of DNA to which a transcription factor binds to regulate gene expression), thereby blocking transcription of that gene. thumb|Corepressor Transcription Factor Complex on Regulatory Element

== Function ==

=== Prokaryotes ===

In prokaryotes, the term corepressor is used to denote the activating ligand of a repressor protein. For example, the ''E. coli'' tryptophan repressor (TrpR) is only able to bind to DNA and repress transcription of the ''trp'' operon when its corepressor tryptophan is bound to it. TrpR in the absence of tryptophan is known as an aporepressor and is inactive in repressing gene transcription.<ref name="pmid9022683">{{cite journal | vauthors = Evans PD, Jaseja M, Jeeves M, Hyde EI | title = NMR studies of the Escherichia coli Trp repressor.trpRs operator complex | journal = Eur. J. Biochem. | volume = 242 | issue = 3 | pages = 567–75 |date=December 1996 | pmid = 9022683 | doi = 10.1111/j.1432-1033.1996.0567r.x | doi-access = }}</ref> Trp operon encodes enzymes responsible for the synthesis of tryptophan. Hence TrpR provides a negative feedback mechanism that regulates the biosynthesis of tryptophan.

In short tryptophan acts as a corepressor for its own biosynthesis.<ref name="isbn0-393-93447-0">{{cite book | vauthors = Foster JB, Slonczewski J | title = Microbiology: An Evolving Science | edition = Second | publisher = W. W. Norton & Company | location = New York | year = 2010 | isbn = 978-0-393-93447-2 }}</ref>

=== Eukaryotes ===

In eukaryotes, a corepressor is a protein that binds to transcription factors.<ref name="pmid9806345">{{cite journal | author = Jenster G | title = Coactivators and corepressors as mediators of nuclear receptor function: an update | journal = Mol. Cell. Endocrinol. | volume = 143 | issue = 1–2 | pages = 1–7 |date=August 1998 | pmid = 9806345 | doi = 10.1016/S0303-7207(98)00145-2 | s2cid = 26244186 }}</ref> In the absence of corepressors and in the presence of coactivators, transcription factors upregulate gene expression. Coactivators and corepressors compete for the same binding sites on transcription factors. A second mechanism by which corepressors may repress transcriptional initiation when bound to transcription factor/DNA complexes is by recruiting histone deacetylases which catalyze the removal of acetyl groups from lysine residues. This increases the positive charge on histones which strengthens the electrostatic attraction between the positively charged histones and negatively charged DNA, making the DNA less accessible for transcription.<ref name="Lazar_2003">{{cite journal | author = Lazar MA | title = Nuclear receptor corepressors | journal = Nucl Recept Signal | volume = 1 | pages = e001 | year = 2003 | pmid = 16604174 | pmc = 1402229 | doi = 10.1621/nrs.01001 }}</ref><ref name="Goodson_2005">{{cite journal |vauthors=Goodson M, Jonas BA, Privalsky MA|title=Corepressors: custom tailoring and alterations while you wait|journal= Nucl Recept Signal |volume= 3 |issue= Oct 21 |pages= e003 |year= 2005|article-number=nrs.03003 | doi = 10.1621/nrs.03003 |pmid= 16604171 |pmc=1402215}}</ref>

In humans several dozen to several hundred corepressors are known, depending on the level of confidence with which the characterisation of a protein as a corepressors can be made.<ref name="pmid20965969">{{cite journal | vauthors = Schaefer U, Schmeier S, Bajic VB | title = TcoF-DB: dragon database for human transcription co-factors and transcription factor interacting proteins | journal = Nucleic Acids Res. | volume = 39 | issue = Database issue | pages = D106–10 |date=January 2011 | pmid = 20965969 | pmc = 3013796 | doi = 10.1093/nar/gkq945 }}</ref>

== Examples of corepressors ==

=== NCoR === NCoR (nuclear receptor co-repressor) directly binds to the D and E domains of nuclear receptors and represses their transcriptional activity.<ref name=":14">{{Citation|last=Bolander|first=Franklyn F.|title=Hormonally Regulated Transcription Factors|date=2004|url=https://linkinghub.elsevier.com/retrieve/pii/B9780121112325500130|work=Molecular Endocrinology|pages=387–443|publisher=Elsevier|language=en|doi=10.1016/b978-012111232-5/50013-0|isbn=978-0-12-111232-5|access-date=2020-10-25|url-access=subscription}}</ref><ref name=":15">{{Cite journal|last=Chinnadurai|first=G|date=February 2002|title=CtBP, an Unconventional Transcriptional Corepressor in Development and Oncogenesis|journal=Molecular Cell|language=en|volume=9|issue=2|pages=213–224|doi=10.1016/S1097-2765(02)00443-4|pmid=11864595|doi-access=free}}</ref><ref name=":16">{{Citation|last=Kammer|first=Gary M.|title=Estrogen, Signal Transduction, and Systemic Lupus Erythematosus: Molecular Mechanisms|date=2004|url=https://linkinghub.elsevier.com/retrieve/pii/B9780124409057503753|work=Principles of Gender-Specific Medicine|pages=1082–1092|publisher=Elsevier|language=en|doi=10.1016/b978-012440905-7/50375-3|isbn=978-0-12-440905-7|access-date=2020-10-25|url-access=subscription}}</ref> Class I histone deacetylases are recruited by NCoR through SIN3, and NCoR directly binds to class II histone deacetylases.<ref name=":14" /><ref name=":16" /><ref>{{Cite journal|last1=Kadamb|first1=Rama|last2=Mittal|first2=Shilpi|last3=Bansal|first3=Nidhi|last4=Batra|first4=Harish|last5=Saluja|first5=Daman|date=August 2013|title=Sin3: Insight into its transcription regulatory functions|url=https://linkinghub.elsevier.com/retrieve/pii/S0171933513000575|journal=European Journal of Cell Biology|language=en|volume=92|issue=8–9|pages=237–246|doi=10.1016/j.ejcb.2013.09.001|pmid=24189169|url-access=subscription}}</ref>

=== Silencing mediator for retinoid and thyroid-hormone receptor=== SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), also known as NCoR2, is an alternatively spliced SRC-1(steroid receptor coactivator-1).<ref name=":14" /><ref name=":15" /> It is negatively and positively affected by MAPKKK (mitogen activated protein kinase kinase kinase) and casein kinase 2 phosphorylation, respectively.<ref name=":14" /> SMRT has two major mechanisms: first, similar to NCoR, SMRT also recruits class I histone deacetylases through SIN3 and directly binds to class II histone deacetylases.<ref name=":14" /> Second, it binds and sequesters components of the general transcriptional machinery, such as transcription factor II B.<ref name=":14" /><ref name=":16" />

== Role in biological processes == Corepressors are known to regulate transcription through different activation and inactivation states.<ref name=":0">{{Cite journal|last=Rosenfeld|first=M. G.|date=2006-06-01|title=Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response|journal=Genes & Development|language=en|volume=20|issue=11|pages=1405–1428|doi=10.1101/gad.1424806|pmid=16751179|issn=0890-9369|doi-access=free}}</ref><ref name=":1">{{Cite journal|last1=Battaglia|first1=Sebastiano|last2=Maguire|first2=Orla|last3=Campbell|first3=Moray J.|date=2010|title=Transcription factor co-repressors in cancer biology: roles and targeting|url= |journal=International Journal of Cancer|volume=126|issue=11|language=en|pages=2511–9|doi=10.1002/ijc.25181|pmc=2847647|pmid=20091860}}</ref>

NCoR and SMRT act as a corepressor complex to regulate transcription by becoming activated once the ligand is bound.<ref name=":0" /><ref name=":1" /><ref name=":2">{{Cite journal|last1=Christian|first1=Mark|last2=White|first2=Roger|last3=Parker|first3=Malcolm G.|date=August 2006|title=Metabolic regulation by the nuclear receptor corepressor RIP140|url=https://linkinghub.elsevier.com/retrieve/pii/S1043276006001056|journal=Trends in Endocrinology & Metabolism|language=en|volume=17|issue=6|pages=243–250|doi=10.1016/j.tem.2006.06.008|pmid=16815031|s2cid=45870845|url-access=subscription}}</ref><ref name=":3">{{Cite journal|last1=Ogawa|first1=S.|last2=Lozach|first2=J.|last3=Jepsen|first3=K.|last4=Sawka-Verhelle|first4=D.|last5=Perissi|first5=V.|last6=Sasik|first6=R.|last7=Rose|first7=D. W.|last8=Johnson|first8=R. S.|last9=Rosenfeld|first9=M. G.|last10=Glass|first10=C. K.|date=2004-10-05|title=A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation|journal=Proceedings of the National Academy of Sciences|language=en|volume=101|issue=40|pages=14461–14466|doi=10.1073/pnas.0405786101|issn=0027-8424|pmc=521940|pmid=15452344|bibcode=2004PNAS..10114461O|doi-access=free}}</ref> Knockouts of NCoR resulted in embryo death, indicating its importance in erythrocytic, thymic, and neural system development.<ref name=":3" /><ref name=":4">{{Cite journal|last1=Jepsen|first1=Kristen|last2=Hermanson|first2=Ola|last3=Onami|first3=Thandi M|last4=Gleiberman|first4=Anatoli S|last5=Lunyak|first5=Victoria|last6=McEvilly|first6=Robert J|last7=Kurokawa|first7=Riki|last8=Kumar|first8=Vivek|last9=Liu|first9=Forrest|last10=Seto|first10=Edward|last11=Hedrick|first11=Stephen M|date=September 2000|title=Combinatorial Roles of the Nuclear Receptor Corepressor in Transcription and Development|journal=Cell|language=en|volume=102|issue=6|pages=753–763|doi=10.1016/S0092-8674(00)00064-7|pmid=11030619|s2cid=15645977|doi-access=free}}</ref>

Mutations in certain corepressors can result in deregulation of signals.<ref name=":1" /> SMRT contributes to cardiac muscle development, with knockouts of the complex resulting in less developed muscle and improper development.<ref name=":1" />

NCoR has also been found to be an important checkpoint in processes such as inflammation and macrophage activation.<ref name=":3" />

Recent evidence also suggests the role of corepressor RIP140 in metabolic regulation of energy homeostasis.<ref name=":2" />

== Clinical significance ==

=== Diseases === Since corepressors participate and regulate a vast range of gene expression, it is not surprising that aberrant corepressor activities can cause diseases.<ref>{{Cite journal|last=Privalsky|first=Martin L.|date=March 2004|title=The Role of Corepressors in Transcriptional Regulation by Nuclear Hormone Receptors|url=http://dx.doi.org/10.1146/annurev.physiol.66.032802.155556|journal=Annual Review of Physiology|volume=66|issue=1|pages=315–360|doi=10.1146/annurev.physiol.66.032802.155556|pmid=14977406|issn=0066-4278|url-access=subscription}}</ref>

Acute myeloid leukemia (AML) is a highly lethal blood cancer characterized by uncontrolled myeloid cell growth.<ref name=":6">{{Cite journal|last1=Tiacci|first1=E.|last2=Grossmann|first2=V.|last3=Martelli|first3=M. P.|last4=Kohlmann|first4=A.|last5=Haferlach|first5=T.|last6=Falini|first6=B.|date=2011-12-30|title=The corepressors BCOR and BCORL1: two novel players in acute myeloid leukemia|journal=Haematologica|volume=97|issue=1|pages=3–5|doi=10.3324/haematol.2011.057901|pmid=22210327|pmc=3248923|issn=0390-6078|doi-access=free}}</ref> Two homologous corepressor genes, BCOR (BCL6 corepressor) and BCORL1, are recurrently mutated in AML patients.<ref name=":7">{{Cite journal|last1=Grossmann|first1=Vera|last2=Tiacci|first2=Enrico|last3=Holmes|first3=Antony B.|last4=Kohlmann|first4=Alexander|last5=Martelli|first5=Maria Paola|last6=Kern|first6=Wolfgang|last7=Spanhol-Rosseto|first7=Ariele|last8=Klein|first8=Hans-Ulrich|last9=Dugas|first9=Martin|last10=Schindela|first10=Sonja|last11=Trifonov|first11=Vladimir|date=2011-12-01|title=Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype|journal=Blood|volume=118|issue=23|pages=6153–6163|doi=10.1182/blood-2011-07-365320|pmid=22012066|issn=0006-4971|doi-access=free}}</ref><ref name=":8">{{Cite journal|last1=Li|first1=Meng|last2=Collins|first2=Roxane|last3=Jiao|first3=Yuchen|last4=Ouillette|first4=Peter|last5=Bixby|first5=Dale|last6=Erba|first6=Harry|last7=Vogelstein|first7=Bert|last8=Kinzler|first8=Kenneth W.|last9=Papadopoulos|first9=Nickolas|last10=Malek|first10=Sami N.|date=2011-11-24|title=Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia|journal=Blood|volume=118|issue=22|pages=5914–5917|doi=10.1182/blood-2011-05-356204|pmid=21989985|pmc=3228503|issn=0006-4971|doi-access=free}}</ref> BCOR works with multiple transcription factors and is known to play vital regulatory roles in embryonic development.<ref name=":6" /><ref name=":7" /> Clinical results detected BCOR somatic mutations in ~4% of an unselected group of AML patients, and ~17% in a subset of patients who lack known AML-causing mutations.<ref name=":6" /><ref name=":7" /> Similarly, BCORL1 is a corepressor that regulates cellular processes,<ref>{{Cite journal|last1=Pagan|first1=Julia K.|last2=Arnold|first2=Jeremy|last3=Hanchard|first3=Kim J.|last4=Kumar|first4=Raman|last5=Bruno|first5=Tiziana|last6=Jones|first6=Mathew J. K.|last7=Richard|first7=Derek J.|last8=Forrest|first8=Alistair|last9=Spurdle|first9=Amanda|last10=Verdin|first10=Eric|last11=Crossley|first11=Merlin|date=2007-03-22|title=A Novel Corepressor, BCoR-L1, Represses Transcription through an Interaction with CtBP|journal=Journal of Biological Chemistry|volume=282|issue=20|pages=15248–15257|doi=10.1074/jbc.m700246200|pmid=17379597|issn=0021-9258|doi-access=free}}</ref> and was found to be mutated in ~6% of tested AML patients.<ref name=":6" /><ref name=":8" /> These studies point out a strong association between corepressor mutations and AML. Further corepressor research may reveal potential therapeutic targets for AML and other diseases.

=== Therapeutic Potential === Corepressors present many potential avenues for drugs to target a vast range of diseases.<ref>{{Cite journal|last1=Vaiopoulos|first1=Aristeidis G.|last2=Kostakis|first2=Ioannis D.|last3=Athanasoula|first3=Kalliopi Ch.|last4=Papavassiliou|first4=Athanasios G.|date=June 2012|title=Targeting transcription factor corepressors in tumor cells|journal=Cellular and Molecular Life Sciences|language=en|volume=69|issue=11|pages=1745–1753|doi=10.1007/s00018-012-0986-5|pmid=22527719|s2cid=16407925|issn=1420-682X|pmc=11114811}}</ref>

BCL6 upregulation is observed in cancers such as diffuse large B-cell lymphomas (DLBCLs),<ref name=":9">{{Cite journal|last1=Cerchietti|first1=Leandro C.|last2=Ghetu|first2=Alexandru F.|last3=Zhu|first3=Xiao|last4=Da Silva|first4=Gustavo F.|last5=Zhong|first5=Shijun|last6=Matthews|first6=Marilyn|last7=Bunting|first7=Karen L.|last8=Polo|first8=Jose M.|last9=Farès|first9=Christophe|last10=Arrowsmith|first10=Cheryl H.|last11=Yang|first11=Shao Ning|date=April 2010|title=A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo|url= |journal=Cancer Cell|language=en|volume=17|issue=4|pages=400–411|doi=10.1016/j.ccr.2009.12.050|pmc=2858395|pmid=20385364}}</ref><ref name=":10">{{Cite journal|last1=Cerchietti|first1=Leandro C.|last2=Yang|first2=Shao Ning|last3=Shaknovich|first3=Rita|last4=Hatzi|first4=Katerina|last5=Polo|first5=Jose M.|last6=Chadburn|first6=Amy|last7=Dowdy|first7=Steven F.|last8=Melnick|first8=Ari|date=2009-04-09|title=A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo|url=https://ashpublications.org/blood/article/113/15/3397/24984/A-peptomimetic-inhibitor-of-BCL6-with-potent|journal=Blood|language=en|volume=113|issue=15|pages=3397–3405|doi=10.1182/blood-2008-07-168773|issn=0006-4971|pmc=2668844|pmid=18927431}}</ref><ref name=":11">{{Cite journal|last1=Parekh|first1=Samir|last2=Privé|first2=Gilbert|last3=Melnick|first3=Ari|date=January 2008|title=Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas|url= |journal=Leukemia & Lymphoma|language=en|volume=49|issue=5|pages=874–882|doi=10.1080/10428190801895345|issn=1042-8194|pmc=2748726|pmid=18452090}}</ref><ref name=":12">{{Cite journal|last1=Yasui|first1=Takeshi|last2=Yamamoto|first2=Takeshi|last3=Sakai|first3=Nozomu|last4=Asano|first4=Kouhei|last5=Takai|first5=Takafumi|last6=Yoshitomi|first6=Yayoi|last7=Davis|first7=Melinda|last8=Takagi|first8=Terufumi|last9=Sakamoto|first9=Kotaro|last10=Sogabe|first10=Satoshi|last11=Kamada|first11=Yusuke|date=September 2017|title=Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design|journal=Bioorganic & Medicinal Chemistry|language=en|volume=25|issue=17|pages=4876–4886|doi=10.1016/j.bmc.2017.07.037|pmid=28760529|doi-access=free}}</ref> colorectal cancer,<ref>{{Cite journal|last1=Sena|first1=Paola|last2=Mariani|first2=Francesco|last3=Benincasa|first3=Marta|last4=De Leon|first4=Maurizio Ponz|last5=Di Gregorio|first5=Carmela|last6=Mancini|first6=Stefano|last7=Cavani|first7=Francesco|last8=Smargiassi|first8=Alberto|last9=Palumbo|first9=Carla|last10=Roncucci|first10=Luca|date=January 2014|title=Morphological and quantitative analysis of BCL6 expression in human colorectal carcinogenesis|journal=Oncology Reports|language=en|volume=31|issue=1|pages=103–110|doi=10.3892/or.2013.2846|pmid=24220798|issn=1021-335X|doi-access=free|hdl=11380/1011113|hdl-access=free}}</ref><ref>{{Cite journal|last1=Sun|first1=Naihui|last2=Zhang|first2=Liang|last3=Zhang|first3=Chongguang|last4=Yuan|first4=Yuan|date=December 2020|title=miR-144-3p inhibits cell proliferation of colorectal cancer cells by targeting BCL6 via inhibition of Wnt/β-catenin signaling|url= |journal=Cellular & Molecular Biology Letters|language=en|volume=25|issue=1|pages=19|doi=10.1186/s11658-020-00210-3|issn=1425-8153|pmc=7079415|pmid=32206063 |doi-access=free }}</ref> and lung cancer.<ref>{{Cite journal|last1=Deb|first1=Dhruba|last2=Rajaram|first2=Satwik|last3=Larsen|first3=Jill E.|last4=Dospoy|first4=Patrick D.|last5=Marullo|first5=Rossella|last6=Li|first6=Long Shan|last7=Avila|first7=Kimberley|last8=Xue|first8=Fengtian|last9=Cerchietti|first9=Leandro|last10=Minna|first10=John D.|last11=Altschuler|first11=Steven J.|date=2017-06-01|title=Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers|url= |journal=Cancer Research|language=en|volume=77|issue=11|pages=3070–3081|doi=10.1158/0008-5472.CAN-15-3052|issn=0008-5472|pmc=5489259|pmid=28377453}}</ref> BCL-6 corepressor, SMRT, NCoR, and other corepressors are able to interact with and transcriptionally repress BCL6.<ref name=":9" /><ref name=":10" /><ref name=":11" /><ref name=":12" /> Small-molecule compounds, such as synthetic peptides that target BCL6 and corepressor interactions,<ref name=":9" /><ref name=":10" /> as well as other protein-protein interaction inhibitors,<ref name=":12" /> have been shown to effectively kill cancer cells.

Activated liver X receptor (LXR) forms a complex with corepressors to suppress the inflammatory response in rheumatoid arthritis, making LXR agonists like GW3965 a potential therapeutic strategy.<ref>{{Cite journal|last1=Venteclef|first1=N.|last2=Jakobsson|first2=T.|last3=Ehrlund|first3=A.|last4=Damdimopoulos|first4=A.|last5=Mikkonen|first5=L.|last6=Ellis|first6=E.|last7=Nilsson|first7=L.-M.|last8=Parini|first8=P.|last9=Janne|first9=O. A.|last10=Gustafsson|first10=J.-A.|last11=Steffensen|first11=K. R.|date=2010-02-15|title=GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXR in the hepatic acute phase response|journal=Genes & Development|language=en|volume=24|issue=4|pages=381–395|doi=10.1101/gad.545110|issn=0890-9369|pmc=2816737|pmid=20159957}}</ref><ref>{{Cite journal|last1=Yoon|first1=Chong-Hyeon|last2=Kwon|first2=Yong-Jin|last3=Lee|first3=Sang-Won|last4=Park|first4=Yong-Beom|last5=Lee|first5=Soo-Kon|last6=Park|first6=Min-Chan|date=January 2013|title=Activation of Liver X Receptors Suppresses Inflammatory Gene Expressions and Transcriptional Corepressor Clearance in Rheumatoid Arthritis Fibroblast Like Synoviocytes|url=http://link.springer.com/10.1007/s10875-012-9799-4|journal=Journal of Clinical Immunology|language=en|volume=33|issue=1|pages=190–199|doi=10.1007/s10875-012-9799-4|pmid=22990668|s2cid=15965750|issn=0271-9142|url-access=subscription}}</ref> Ursodeoxycholic acid (UDCA), by upregulating the corepressor CREBZF (small heterodimer partner interacting leucine zipper protein, SMILE), inhibits the expression of IL-17, an inflammatory cytokine, and suppresses Th17 cells, both implicated in rheumatoid arthritis.<ref name=":13">{{Cite journal|last1=Lee|first1=Eun-Jung|last2=Kwon|first2=Jeong-Eun|last3=Park|first3=Min-Jung|last4=Jung|first4=Kyung-Ah|last5=Kim|first5=Da-Som|last6=Kim|first6=Eun-Kyung|last7=Lee|first7=Seung Hoon|last8=Choi|first8=Jong Young|last9=Park|first9=Sung-Hwan|last10=Cho|first10=Mi-La|date=August 2017|title=Ursodeoxycholic acid attenuates experimental autoimmune arthritis by targeting Th17 and inducing pAMPK and transcriptional corepressor SMILE|url=https://linkinghub.elsevier.com/retrieve/pii/S0165247816302401|journal=Immunology Letters|language=en|volume=188|pages=1–8|doi=10.1016/j.imlet.2017.05.011|pmid=28539269|url-access=subscription}}</ref><ref>{{Cite journal|last1=Sarkar|first1=Sujata|last2=Fox|first2=David A.|date=May 2010|title=Targeting IL-17 and Th17 Cells in Rheumatoid Arthritis|url=https://linkinghub.elsevier.com/retrieve/pii/S0889857X10000189|journal=Rheumatic Disease Clinics of North America|language=en|volume=36|issue=2|pages=345–366|doi=10.1016/j.rdc.2010.02.006|pmid=20510238|url-access=subscription}}</ref> This effect is dose-dependent in humans, and UCDA is thought to be another prospective agent of rheumatoid arthritis therapy.<ref name=":13" />

== See also == * Transcription coregulator * TcoF-DB

== References == {{Reflist}}

== External links == * {{MeSH name|Co-Repressor+Proteins}}

{{Transcription}} {{Transcription coregulators}}

Category:Gene expression Category:Transcription coregulators