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MINIREVIEWMixed lineage leukemia: roles in gene expression, hormonesignaling and mRNA processingKhairul I. Ansari and Subhrangsu S. MandalDepartment of Chemistry and Biochemistry, The University of Texas at Arlington, TX, USAIntroductionIn eukaryotes, gene regulation is a complex process [1].In addition to RNA polymerase II (RNAPII), there arenumerous other transcription factors and regulatoryproteins that coordinate with RNAPII to accuratelyexpress a particular gene under a specific cellular envi-ronment. In higher organisms, DNA is complexed withvarious histones and other nuclear proteins in the formof compact chromatins. These chromatins are not easilyaccessible to gene expression machinery unless they aremodified or remodeled [1]. Intense research over thepast two decades has led to the discovery of variouschromatin-remodeling factors and histone-modifyingenzymes that modulate chromatin structures to facilitategene expression [1]. Histone methyltransferases (HMTs)are key enzymes that introduce methyl groups into thelysine side chain of histone proteins and regulate geneactivation and silencing (Fig. 1). Histone H3 lysine 4(H3K4) methylation is an evolutionarily conservedmark with fundamental roles in gene activation [2]. Set1is the only H3K4-specific HMT present in yeast and is acomponent of a multiprotein complex called COM-PASS [3]. In higher eukaryotes, H3K4-specific HMTsare diverged with increased structural and functionalcomplexity [4]. In humans, there are at least eightH3K4-specific HMTs that include mixed lineage leuke-mia 1 (MLL1), MLL2, MLL3, MLL4, MLL5, hSet1A,Keywordsepigenetics; estrogen receptor; geneexpression; histone methyltransferase;hormone signaling; mixed lineage leukemia;mRNA processing; NR-box; nuclearreceptor; SET domainCorrespondenceS. S. Mandal, Gene Regulation and DiseaseResearch Laboratory, Department ofChemistry and Biochemistry, The Universityof Texas at Arlington, Arlington, TX 76019,USAFax: +1 817 272 3808Tel: +1 817 272 3804E-mail: smandal@uta.edu(Received 14 November 2009, revised 16January 2010, accepted 28 January 2010)doi:10.1111/j.1742-4658.2010.07606.xMixed lineage leukemias (MLLs) are an evolutionarily conserved trithoraxfamily of human genes that play critical roles in HOX gene regulation andembryonic development. MLL1 is well known to be rearranged in myeloidand lymphoid leukemias in children and adults. There are several MLLfamily proteins such as MLL1, MLL2, MLL3, MLL4, MLL5, Set1A andSet1B, and each possesses histone H3 lysine 4 (H3K4)-specific methyltrans-ferase activity and has critical roles in gene activation and epigenetics.Although MLLs are recognized as major regulators of gene activation,their mechanism of action, target genes and the distinct functions of differ-ent MLLs remain elusive. Recent studies demonstrate that besides H3K4methylation and HOX gene regulation, MLLs have much wider roles ingene activation and regulate diverse other genes. Interestingly, severalMLLs interact with nuclear receptors and have critical roles in steroid-hormone-mediated gene activation and signaling. In this minireview, wesummarize recent advances in understanding the roles of MLLs in generegulation and hormone signaling and highlight their potential roles inmRNA processing.AbbreviationsASCOM, activating signal cointegrator-2 (ASC2) complex; CBP, CREB-binding domain; CGBP, CpG-binding protein; ER, estrogen receptor;H3K4, histone H3 lysine 4; HMT, histone methyltransferase; HSC, hematopoietic stem cell; LXR, liver X receptor; MLL, mixed lineageleukemia; NR, nuclear receptor; RAR, retinoic acid receptor; RNAPII, RNA polymerase II; SF, splicing factor.1790 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBShSet1B and ASH1 [5]. The high conservation and multi-plicity of MLLs suggests that they have crucial anddistinct functions in the cell, although their detailedmechanisms of action are largely unknown. Recent stud-ies have demonstrated that MLLs are key epigenetic reg-ulators of diverse gene types associated with cell-cycleregulation, embryogenesis and development. MLLs alsointeract with nuclear receptors (NR) and coordinatehormone-dependent gene regulation, suggesting theircrucial roles in reproduction, organogenesis and disease[6]. In this minireview, we summarize recent advance-ments addressing the roles of MLLs in human gene reg-ulation, hormone signaling and mRNA processing.MLLs are human H3K4-specificmethyltransferasesIt is well-known that MLLs are often rearranged,amplified or deleted in different types of cancer [7–10].MLLs are master regulators of HOX genes, which arekey players in embryogenesis and development.Because of their importance in gene regulation and dis-ease, MLLs have been isolated from human cells andtheir protein–protein interaction profiles and enzymaticactivities have been characterized in detail [5,11]. Thesestudies demonstrate that MLL1, MLL2, MLL3,MLL4, Set1A and Set1B exist as distinct multiproteincomplexes with several common subunits includingAsh2, Wdr5, Rbbp5 and Dpy30. Each of these MLLsand Set1 contains a catalytic SET domain responsiblefor their HMT activity (Fig. 2). Recently, we demon-strated that human CpG-binding protein (CGBP)interacts with MLL1, MLL2 and human Set1, and is acore component of these HMT complexes [12]. Inaddition to the core components, MLLs interact withvarious unique components including chromatin-remodeling factors, mRNA-processing factors andnuclear hormone receptors. Dou et al. [5] purified anH3 H4H2AH2BK9K4MeMeMeMeMeK79K36K27K20K120MeK119H3 H4H2AH2BK9K4H3MLLMeMeMeMeMeMeMeMeMeMeK79K36K27ActivationActivationSilencingK20K120UbH2BMeMeH4SilencingH2AK119UbNucleosomeFig. 1. Mixed lineage leukemias (MLL) arehistone H3 at lysine 4-specific methylasesthat regulate gene activation.MLL3 MLL5 MLL1 MLL4 MLL2 CXXC zf FYRC FYRN BROMO HMG AT-Hook PHD NR-box (LXXLL) Taspase1 RING SET Fig. 2. Domain structures of mixed lineage leukemias (MLLs). AT-hook is a DNA-binding domain. Bromodomains (BROMO) are involved inthe recognition of acetylated lysine residues in histone tails. CXXC-zf is a Zn-finger domain involved in protein–protein interactions. FYRC andFYRN domains are involved in heterodimerization between MLLNand MLLCterminal fragments. High-mobility group (HMG) domains areinvolved in binding DNA with low sequence specificity. LXXLL domains (also known as the NR box) are involved in interaction with nuclearreceptor (NR). Plant homodomain (PHD) and RING fingers are usually involved in protein–protein interactions. The SET domain is responsiblefor histone lysine methylation. The Taspase 1 site is the proteolytic site for the protease Taspase 1. Some other domains including frequentcoiled coil domains that mediate homo-oligomerization are not shown.K. I. Ansari and S. S. Mandal Biochemical functions of MLLFEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS 1791MLL1 complex that contains histone acetyl transfer-ase, MOF, host cell factors, HCF1 and HCF2. Simi-larly, Menin, which is a product of the MEN1 tumorsuppressor gene, is an interacting component of MLL1and MLL2 complexes [13].MLL-associated HMT activity appears to be func-tional only in the context of their multiprotein com-plexes and each MLL-interacting protein plays adistinct role in regulating MLL-mediated histonemethylation and gene activation. For example, Wdr5binds to dimethylated H3K4 and knockdown of Wdr5results in decreased expression of MLL1 target HOXgenes without affecting binding of MLL1 complexes tothe promoters [14]. Similarly, knockdown of Rbbp5 orAsh2 also reduces the expression of HOX genes with-out affecting the recruitment of MLL1 into their pro-moter [5,15]. Independent studies have demonstratedthat Wdr5, Rbbp5 and Ash2 are essential for HOXgene expression and this requirement lies in the regula-tion of H3K4 dimethylation and trimethylation [16].In vitro reconstitution experiments have demonstratedthat Wdr5, Rbbp5, Ash2 and the catalytic C-terminusof MLL1 (MLL-C) form a functional MLL1 HMTcomplex [5]. The absence of Rbbp5 and Ash2 reducesthe H3K4-specific HMT activity of the MLL1 complexin vitro. Removal of Wdr5 completely abolishes themethylation activity of MLL complex. In contrast toWdr5, Rbbp5 and Ash2, results from our laboratorydemonstrate that knockdown of CGBP abolishes therecruitment of MLL1 into the promoter of its targetHOXA7 gene, affecting H3K4 trimethylation andHOXA7 gene expression [12]. These observations sug-gest that MLL-interacting components have distinctroles in controlling MLL-mediated histone methylationand target gene expression.MLLs are critical for HOX generegulation and embryonic developmentHomeobox genes are a group of evolutionarily con-served genes that encode transcription factors and reg-ulate gene expression during development. There aremore than 200 homeobox genes in vertebrates that areclassified into two major groups, class I and II. Class Ihomeobox-containing genes share a high degree ofidentity and are known as HOX genes. Humanencodes 39 different HOX genes that are clustered infour different groups, HOXA–D, located on chromo-somes 7, 17, 12 and 2, respectively. Based on sequencesimilarities and location within the cluster, HOX genesare further classified into 13 paralogous groups [17].The nature of the body structures depends on the spe-cific combination of HOX gene products and theexpression of specific HOX gene varies at differentstages of development. Therefore, proper regulationand maintenance of HOX genes are essential for nor-mal physiological functions and growth.To understand the developmental function ofMLL1 and its role in HOX gene regulation, severalgroups have used different strategies to disrupt theMLL1 gene. These studies have shown that homo-zygous Mll1 (a murine ortholog of human MLL1)knockout mice die during embryogenesis [18,19].Lethality at embryonic day 10.5 is associated withmultiple patterning defects in neural crest-derivedstructures of the branchial arches, cranial nerves andganglia [18,19]. MLL protein is critical for properregulation of HOX genes during development.Notably, expression of several examined Hox genesis correctly initiated in Mll1-null (Mll1) ⁄ )) mice, butis not sustained as the function of Mll1 becomesnecessary, leading to embryonic lethality [18,19].Mll1-mutant mice also exhibit hematopoietic abnor-malities, associated with decreased expression of anumber of Hox genes (Hoxa7, Hoxa9, Hoxa10,Hoxa4) in the Mll1-mutant fetal liver [20,21]. Theearly embryonic lethality of Mll1 homozygousmutants has prevented detailed analysis of the roleof MLL1 function during adult development andhematopoiesis.Interestingly, deletion of the SET domain (responsi-ble for HMT activity) alone of Mll1 is not lethal andmutant mice are fertile. Homozygous SET domain-truncated mutants exhibit developmental skeletaldefects and alteration in the maintenance of the propertranscription levels of several target Hox loci (suchHoxd4, a5 and a7) during development [22]. Impor-tantly, these changes in gene expression levels areassociated with a reduction of histone H3K4 monome-thylation (H3K4me1) and altered DNA methylationpatterns at the same Hox loci. These results demon-strate an essential role for the MLL-SET domain inchromatin structure and Hox gene regulation in vivo[22]. Using an inducible knockout system, Jude et al.[23] investigated the roles of Mll1 in adult hematopoi-etic stem cells (HSCs) and progenitors. These studiesdemonstrated that Mll1 is essential for the maintenanceof adult HSCs and progenitors, with fetal bone marrowfailure occurring within 3 weeks of Mll1 deletion. HSCslacking Mll1 exhibit ectopic cell-cycle entry resulting inthe depletion of quiescent HSCs, and Mll1 deletionin myelo-erythroid progenitors results in reduced proli-feration and a reduced response to cytokine-inducedcell-cycle entry [23]. Committed lymphoid and myeloidcells no longer require Mll1, indicating Mll1-dependentearly multipotent stages of hematopoiesis [23]. TheseBiochemical functions of MLL K. I. Ansari and S. S. Mandal1792 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBSstudies demonstrate that Mll1 plays selective and inde-pendent roles within the hematopoietic system, main-taining quiescence in HSCs and promoting proliferationin progenitors [23]. Similarly, in an independent studyusing a conditional knockout mouse model, it wasshown that Mll1, although dispensable for the produc-tion of mature adult hematopoietic lineages, plays acritical role in stem cell self-renewal in fetal liver andadult bone marrow [24].The critical role of MLL1 in HOX gene regulation isevident from a simple fibroblast model and HOX geneexpression is dependent on the HMT activities ofMLL [25,26]. Myeloid transformation by MLL oncog-enes is associated with expression of a specific subsetof HOXA genes [27]. Murine primary myeloid progeni-tor cell lines immortalized by five different MLL fusionproteins exhibit a characteristic Hoxa gene expressionprofile and all lines expressed Hoxa7, Hoxa9, Hoxa10and Hoxa11 genes located at the 5¢-end of the Hoxacluster [28]. By contrast, 3¢-end Hoxa genes were vari-ably expressed with periodicity, as evidenced by lowlevels of Hoxa1 , higher levels of Hoxa3 and Hoxa5and the complete absence of Hoxa2, Hoxa4 andHoxa6 expression [28]. These studies also demon-strated that Hoxa7 and Hoxa9 are required forefficient in vitro myeloid immortalization by an MLLfusion protein, but not other leukemogenic fusionproteins [28]. In an independent study, depletion ofTaspase1 (a MLL1-specific protease that cleaves pre-MLL1 peptide to generate functional MLL1 proteinfragments) diminished expression of selected HOXgenes across the HOXA cluster [29]. Despite continu-ous expression of MLL1 throughout hematopoiesis,MLL target genes HOXA7, HOXA9 and MEIS1 areexpressed during early hematopoietic lineages and theirexpression downregulated to undetectable levels duringthe later stages of differentiation [30]. These observa-tions suggest that the associations of either MLL orMLL-associated coregulators with the promoters aremodulated at different stages of development, resultingin differential expression of target HOX genes. Overall,various knockout and cell line studies demonstrate thatMLLs are master players in HOX gene regulation anddevelopment.MLLs are general transcriptionalregulator (beyond HOX genes)Although MLLs are well-recognized as master regula-tors of HOX genes, studies suggest that MLLs playmuch wider roles in regulating the transcription ofdiverse gene types [31–34]. Several approaches havebeen used to investigate MLL target genes. However,it is important to note that the functions of MLLsmay be highly dependent upon the cellular environ-ment (such as the presence of hormones and nutrients),cell types and developmental stages. Analyzing thefunctions of MLLs in gene regulation in a given celllineage is important and may provide crucial informa-tion about the roles of MLLs in that particular cellularenvironment. However, this may underscore muchwider functions of MLLs in other cell types or underdifferent cellular environments and therefore the regu-latory roles of MLLs may not be generalized based oninformation obtained from experiments with a singlecell type.Using a genome-wide promoter binding assay it hasbeen shown that MLL1 and H3K4 trimethylation isenriched at the promoters of transcriptionally activegenes [35]. The overlap of MLL1 binding and H3K4trimethylation reinforces the role of MLL1 as a posi-tive global regulator of gene transcription [35]. MLL1also localizes to microRNA (miRNA) loci that areinvolved in leukemia and hematopoiesis [35]. MLLassociates only with transcriptionally active promotersand therefore is cell-type and differentiation-stage spe-cific [30]. In a separate study, using gene expressionprofiling in murine cell lines (Mll+ ⁄ +and Mll) ⁄ )), itwas shown that Mll1 is associated with both transcrip-tionally active and repressed genes [36]. These studiesalso demonstrated that beyond HOX genes, Mll1 regu-lates diverse other gene types that are involved in dif-ferentiation and organogenesis pathways (such asCOL6A3, DCoH, gremlin, GDID4, GATA-6 andLIMK) [36]. p27kip1 and GAS-1, which are knowntumor suppressor proteins involved in cell-cycle regula-tion, are also found as targets of Mll1 [36]. Mll1 is alsolinked to the expression of a variety of genes linkedwith leukemogenesis and other malignant transforma-tions including HNF-3 ⁄ BF-1, Mlf1, FBJ, Tenascin C,PE31 ⁄ TALLA-1 and tumor protein D52-like gene [36].More recently, Wang et al. [37] performed a genome-wide analysis of H3K4 methylation patterns in wild-type (Mll1+ ⁄ +) and Mll1) ⁄ )mouse embryonic fibro-blasts (MEFs). These studies demonstrated that Mll1is required for the H3K4 trimethylation of < 5% ofpromoters carrying this modification [37]. AlthoughMll1 is only required for the methylation of a subsetof Hox genes, menin, a component of the Mll1 andMll2 complexes, is required for the overwhelmingmajority of H3K4 methylation at Hox loci [37]. How-ever, the loss of Mll3 ⁄ Mll4 and ⁄ or the Set1 complexeshas little to no effect on the H3K4 methylation of Hoxloci or on their expression levels in these MEFs [37].These observations suggest that different MLLs mayhave distinct functions beyond H3K4 methylation.K. I. Ansari and S. S. Mandal Biochemical functions of MLLFEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS 1793Another surprising but interesting recent observationmay significantly alter the view of transcriptional regu-lation [38]. Using genome-wide analyses in embryonicstem cells (also differentiated cells), Guenther et al.[38] showed that the promoter-proximal nucleosome ofmost of the protein-coding genes is trimethylated atH3K4, although it is generally thought to be the markof only transcriptionally active genes. Furthermore,most of the genes considered to be inactive (because oflow transcript levels) experience transcription initiationand associated histone modification [38]. These obser-vations suggest that transcription initiation is a generalphenomenon in most genes and the elongation phaseperhaps contributes significantly to the regulation oftranscript synthesis.In addition to the genome-wide studies, independentstudies from several laboratories demonstrate thatMLLs play critical roles in cell-cycle regulation. Take-da et al. [34] showed that mutation of Taspase 1 resultsin the downregulation of cyclin E, A and B, and upreg-ulation of p16 (an S-phase inhibitor). MLL1 binds tothe promoters of cyclin E1 and E2 and there is amarked reduction in the H3K4 trimethylation level, aswell as MLL1 occupancy at the cyclin E1 and E2 pro-moters in Taspase 1-negative cells [34]. MLLs alsointeract with other cell-cycle regulatory transcriptionfactors such as E2F family proteins. Whereas MLL1interacts with E2F2, E2F4 and E2F6, MLL2 interactswith E2F2, E2F3, E2F5 and E2F6 [34]. Similar toE2Fs, the G1-phase regulator HCF-1 recruits MLL1and Set1 to E2F-responsive promoters and induces his-tone methylation and transcriptional activation duringthe G1phase [39]. Recently, we demonstrated thatMLL1 and H3K4 trimethylation have distinct dynam-ics during cell-cycle progression [40]. MLL1, which isnormally associated with transcriptionally activechromatins in G1, dissociates from condensed mitoticchromatins, migrates from the nucleus to the cyto-plasm and returns at the end of telophase when thenucleus starts to relax. However, the global level ofMLL1 is not affected [40]. We also found that severalMLL target HOX genes (such as HOXA10, HOXA5and HOXB7) are expressed differentially during cell-cycle progression. For example, HOXA10 expression isvery high in the S phase, decreases significantly inG2⁄ M and is completely absent in G1[40]. Expressionof HOXA5 increases from very low levels at the begin-ning of the S phase, reaches a maxima at G2⁄ M,declining sharply to its initial low level and remainingso throughout mitosis and G1. Importantly, MLL1binds to the promoter of these HOX genes as a func-tion of their expression during cell-cycle progression[40]. These observations suggest that although at themicroscopic level, MLLs dissociate from the con-densed nuclear matrix during mitosis, some MLLremains associated with chromatin and maintainsexpression of specific cell-cycle-related genes duringmitosis. Depletion of MLL1 also results in cell-cyclearrest at the G2⁄ M phase and inhibits cellulargrowth, further suggesting its crucial roles in cell-cycle progression [40]. Although the detailed roles ofMLLs and their interacting proteins in cell-cycleregulation are still not clear, multiple lines ofevidence indicate that MLLs play critical roles incell-cycle regulation.In addition to cell-cycle regulatory genes, MLL1plays important roles in the regulation of stress-responsive genes. MLL3 and MLL4 act as a p53 coac-tivator (a tumor suppressor gene) and are required forH3K4 trimethylation and expression of endogenousp53 target genes in response to the DNA-damagingagent, doxorubicin [32]. Expression of p21, a promi-nent p53 target gene, was significantly reduced inMLL3-depleted mice relative to wild-type mice.Although direct interaction of MLLs with p53 leads totranscription activation in vitro [15], Menin mediatesrecruitment of MLLs onto the promoter of p27 andp18 genes affecting their expression [33]. Depletion ofMLL1 leads to p53-dependent growth arrest [31].Recent studies from our laboratory demonstrate thatMLLs are upregulated upon exposure to oxidativestress induced by a common food contaminant myco-toxin, deoxynivalenol [41]. Transcription factor Sp1plays a critical role in deoxynivalenol-mediated upreg-ulation of MLL1. MLL-targeted HOX genes (such asHOXA7) are also upregulated upon exposure todeoxynivalenol and chromatin immunoprecipitationanalysis demonstrated increased binding of MLL1 tothe target HOX gene promoters in the presence ofdeoxynivalenol [41]. These observations indicate thepossible involvement of MLLs in the stress response.The relationship between MLL and stress is furtherstrengthened by observations that several externalstresses (such as exposure to estrogen or flavonoids)induce the rearrangement of MLL1 [42,43]. Similarly,exposure to contraceptive pills increases the risk of leu-kemia in the fetus and infants [44]. These observationssuggest that MLLs and associated diseases are linkedwith different types of stress.MLLs are also found to be associated with the telo-meres. MLLs affect H3K4 methylation and transcrip-tion of telomere in a length-dependent manner [31].RNAi-mediated depletion of MLL in human diploidfibroblasts affects telomere chromatin modification,telomere transcription, telomere capping and inducesthe telomere damage response. Overall, these studiesBiochemical functions of MLL K. I. Ansari and S. S. Mandal1794 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBSdemonstrated that MLLs are not only critical forHOX gene regulation, but also are associated withother types of gene regulation.Are MLLs merely histone methylases ordo they have additional roles in generegulation?Gene expression may have different states: basal, acti-vated (usually stimulated by external stimuli such astemperature, special nutrients, hormones or otherstresses) and repressed transcription (silencing) [1].Although the requirement of general transcription fac-tors is likely to be similar in both the basal and acti-vated transcription environment, the requirement foraccessory factors (activators and coactivators, repres-sors and corepressor) may vary depending on the tran-scription state and cell type. We hypothesize thatalthough all MLLs are H3K4-specific HMTs, theyhave distinct functions during basal and activated tran-scription. H3K4 methylation is likely to be a commonrequirement for both basal and activated transcription.However, in addition to or even independent of theirH3K4-specific HMT activity, MLLs may have differ-ent coregulatory functions during activated (and possi-bly repressed) transcription. Based on some of ourrecent unpublished observations, MLL1 appears to actas a histone methylase during basal transcriptionwhereas MLL2, MLL3 and MLL4 replace MLL1during activated transcription and act as coactivators,at least in selected HOX genes.MLLs contain diverse functional domains (Fig. 2).Studies indicate that the SET domain plays pivotalroles in transcriptional regulation in target genes. Dele-tion of the MLL1 SET domain abolishes its ability toactivate HOX gene expression, indicating key roles forH3K4 methylation by the SET domain during transac-tivation [45]. Kinetic studies revealed that the reactionleading to H3K4 dimethylation involves the transientaccumulation of a monomethylated species, suggestingthat the MLL1 core complex uses a nonprocessivemechanism to catalyze multiple lysine methylation [46].Nevertheless, methylation of histones by MLLs playskey roles in the transactivation of target genes. Ingeneral, MLL1 interacts and colocalizes with RNAPIIprimarily at the promoter during transcription. Insome cases, MLL1 is also found to be associatedwithin the coding region of a subset of actively tran-scribed target genes and loss of MLL1 functionimpairs RNAPII distribution [30]. These observationsindicate that an intimate association of MLL andRNAPII is required for transcription initiation and ⁄ orthe elongation of MLL target genes [30,47].In addition to their direct roles in gene activationvia H3K4 methylation, MLLs interact with other chro-matin modifying enzymes and coregulators (see below)and facilitate gene expression. For example, MLL1complex physically interacts with acetyl transferaseMOF which remodels chromatin by histone acetylationand charge neutralization [15]. Both H3K4 methylationand H4K16 acetyl transferase activities are requiredfor optimal transactivation of the MLL1 targetHOXA9 gene [15]. The MLL1 C-terminal domain isalso an interaction partner for histone acetyl transfer-ase CREB-binding protein (CBP) and the INI1 subunitof SWI ⁄ SNF chromatin remodeling complexes, sug-gesting further coordination of MLL complexes in his-tone methylation, acetylation, chromatin remodelingand mRNA synthesis [48,49].MLL1 fusion proteins are also associated with vari-ous chromatin remodeling factors and transcriptionalregulators. For example, MLL1 is fused to ace-tyl transferase CBP and related protein P300, espe-cially in therapy-induced secondary leukemia.Structure–function analysis demonstrated that bromoand acetyl transferase domains are necessary and suffi-cient for the oncogenic transformation of respectiveproteins [50,51]. The MLL fusion protein MLL–AF10interacts with SWI ⁄ SNF complex via GAS41 and INI1[52]. The MLL fusion protein MLL–ENL also associ-ates and cooperates with SWI ⁄ SNF complexes to acti-vate transcription of HOX genes [53]. Furthermore,ENL (MLL fusion partner) is associated not only withMLL fusion protein AF4 family members (AF4,AF5q31, LAF4) but also with positive transcriptionelongation factor-b and histone H3K79-specific meth-yltransferase DOT1L [54,55]. Interestingly, the MLLfusion partner AF10 binds to DOT1L and thatDOT1L recruitment was necessary for the oncogenictransforming activity of MLL–AF10 [55]. H3K79methylation was dramatically increased in the HOXA9gene upon activation by MLL–ENL. In summary,these studies suggest that coordination of histone mod-ification (including methylation and acetylation) andnucleosome remodeling by MLL complexes in bothwild-type and MLL fusion proteins results in balancedtransactivation of target genes.In addition to the catalytic SET domain, severalother protein–DNA or protein–protein interactingdomains present in MLL peptides are functionallyinvolved in MLL-mediated transactivation of the targetgene. For example, the AT-hook DNA-bindingdomains present in MLLs indicate that they mediatetargeting of MLLs to their nuclear site and permit spe-cific binding to the minor groove of AT-rich DNA [56].Deletion of AT-hook motifs substantially impairs theK. I. Ansari and S. S. Mandal Biochemical functions of MLLFEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS 1795transforming effects of MLL–ENL on primary myeloidprogenitors [57,58]. In addition to the AT-hook, theCXXC finger domain present in the N-terminus ofMLL mediates selective binding of MLL to nonmethy-led-CpG DNA [59]. The CXXC domain recruits MLL–ENL to nonmethylated CpG DNA sites in vitro andaffects transactivation of target genes in vivo [59]. Ourrecent study showed that CGBP containing CXXCDNA-binding motifs interacts with MLLs and recruitsthem into the promoter of the HOXA7 gene [12]. DNAmethyltransferase homology regions present in MLL1may have an affinity for AT- and GC-rich sequencesand play critical roles in the recruitment of MLL totarget genes. In addition to AT-hooks and the CpG-binding activity of MLL and its interacting proteinCGBP, recruitment of MLLs to a target gene promotermay be influenced by various other interacting proteinssuch as Wdr5 and Menin [5,13,30]. Wdr5 recognizesthe histone H3K4 methyl-mark introduced by MLL1and it has therefore been suggested that Wdr5 ensuresthe processivity of MLL1-mediated histone modifica-tion [60]. Similar to Wdr5, Menin binds to the N-termi-nus of MLL1 and facilitates recruitment of MLL1, andseveral oncogenic MLL1 fusion proteins, to target genepromoters [61]. Menin can be recruited to DNA viainteractions with sequence-specific transcription factorssuch as NRs (discussed below) and with the chromatin-associated factor lens epithelium-derived growth factor,a chromatin-associated protein required for both MLL-dependent transcription and leukemic transformation.Thus, diverse DNA-binding domains, protein–proteininteraction modes and pre-existing chromatin modifica-tions may facilitate the binding of MLLs, depending onthe context and cell types, to facilitate transcriptionactivation. The detailed functions of other MLL1domains are summarized Cosgrove and Patel in thisminireview series [62].MLLs are key players in nuclearreceptor-mediated gene activation andhormone signalingNRs are a special class of transcription factors thatare responsible for sensing the presence of hormonesin cells and transducing signals for various cellularpathways, including the activation of hormone-respon-sive genes in a hormone-dependent manner [63]. MostNRs share a common structural organization thatincludes a DNA-binding domain, a ligand-bindingdomain and a transactivation domain. The DNA-bind-ing domain is responsible for DNA binding specificityand dimerization, and the ligand-binding domain isresponsible for binding of the ligand and associatedinduced functions. The N-terminal region of NRs con-tains one highly variable transactivation region (AF1)and the C-terminal region contains a conserved trans-activation domain AF2, which undergoes structuralchanges in response to hormones and ultimately resultsin activation of the NR. Activated NRs bind to thepromoters of target genes leading to their activation.It is well-recognized that during ligand-dependenttranscription activation, activated NRs require varioustypes of coregulators (coactivators and corepressors)[64,65]. For example, during transcriptional activationof E2-responsive genes, estrogen receptors (ER) associ-ate with a distinct subset of cofactors, depending onthe target gene, binding affinities and relative abun-dance of these factors in the cells [65]. These coactiva-tors and repressors usually exist in multiple complexes,possess multiple enzymatic activities and (in a simpli-fied view) bridge ERs, to chromatin components suchas histone, to components of the basal transcriptionmachinery or to both [66]. Intense research has identi-fied a large number of cofactors including three mem-bers of the SRC-1 family (SRC-1, SRC-2 ⁄ GRIP1 ⁄ TIF2and SRC-3 ⁄ AIB1 ⁄ ACTR ⁄ pCID ⁄ RAC3 ⁄ TRAM1),CBP, p ⁄ CAF, thyroid hormone receptor protein andvitamin D3 receptors-interacting proteins. Studies havedemonstrated that ASCOM, which consists of MLLsas an interacting component, also participates activelyin E2-mediated gene activation [67,68]. In addition,Menin, which is also a component of MLL1 ⁄ MLL2complexes, acts as a coregulator for ERa and regulatesestrogen-responsive genes [13].MLLs interact with NR via NR boxes and regulategene activationNR coactivators characteristically contain helicalLXXLL or FXXLF motifs (NR box) and interact withthe AF2 domain of the liganded NR [63,64,69].Sequence analysis demonstrates that MLL histonemethylases (MLL1–4) contain one or more NR boxes(Fig. 2). MLL1 contains one NR box, whereas MLL2,-3 and -4 contain three to four, indicating their potentialinteraction with NRs and associated gene regulation.Recent studies demonstrate that MLLs act as coacti-vators for various hormone-responsive genes in aligand-dependent manner. Mo et al. [70] demonstratedthat MLL2 interacts physically with estrogen receptor-alpha (ERa), a critical player in estrogen-mediated geneactivation, via its LXXLL motifs in the presence of thesteroid hormone estrogen. Disruption of the interactionbetween ERa and MLL2 (using MLL2 siRNA) inhibitsestrogen-mediated transactivation of estrogen-respon-sive genes such as cathepsin D and pS2. MLL2 isBiochemical functions of MLL K. I. Ansari and S. S. Mandal1796 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBSrecruited to the promoters of cathepsin D and pS2along with ERa in an E2-dependent manner.In addition to the direct interaction of MLL2 withERa, MLLs may interact with ERs via other MLL-interacting proteins (NR-box containing) such asMenin, ASC2 and INI1, and regulate target gene acti-vation (Fig. 3). Dreijerink et al. [13] showed thatMenin (through its LXXLL domains) interacts withERa, recruits MLL2 complex into the promoter ofestrogen-responsive genes (TFF1 gene) and regulatestheir expression in an estrogen-dependent manner.Menin serves as a critical link between activated ERaand the MLL2–coactivator complex in this process.A similar interaction involving Menin was observed inthe case of peroxisome proliferator-activated receptor(PPARgamma, which generally expresses in severalMEN1-related tumor cells) and regulates their targetgene expression in a ligand-dependent manner [71].In addition to Menin, other components of theMLL complex or MLL-interacting complexes mayrecruit MLLs onto the gene promoter in a ligand-dependent manner. Lee et al. showed that ASCOMcomplexes containing MLL3 or MLL4 are tightly colo-calized in the nucleus [67,72]. Their study also revealedthat the C-terminal SET domain of MLL3 and MLL4directly interacts with INI1, an integral subunit of AT-Pase-dependent chromatin remodeling complexSWI ⁄ SNF [67] and their mutational studies revealedthat both ASCOM and SWI ⁄ SNF complex facilitateeach other binding to the promoter of NR target gene.Thus, these studies suggest that in addition to directinteractions of MLLs with NRs, they interact via vari-ous MLL-interacting components in a ligand-depen-dent manner to regulate NR-mediated gene expression.MLLs interact with different NRs via ASC2complexes and regulate NR target geneactivationA widely studied NR coactivator is activating signalcointegrator-2 (ASC2, also named AIB3, TRBP,TRAP250, NRC, NCOA6 and PRIP) [69]. ASC2 is acoactivator of multiple nuclear receptors including reti-noic acid receptor (RAR), liver X receptors (LXR)+1Wdr5CGBPRbbp5Dpy30NRNRLMLLASC2/INI1Ash2Wdr5MeninCGBPRbbp5Dpy30Ash2LXXLL domain of MLLMeninLASC2NR-coregulatorsASC2/INI1Menin+1Wdr5Wdr5CGBPCGBPRbbp5Dpy30Dpy30NRNRLMLLASC2/INI1Ash2Ash2Wdr5Wdr5MeninMeninCGBPCGBPRbbp5Dpy30Dpy30MLLAsh2Ash2LXXLL domain of MLLMeninLASC2ASC2Chromatin modification/remodelingGene activationNR-coregulators????ASC2/INI1MeninHREFig. 3. Mixed lineage leukemias (MLLs) are coregulators for nuclear receptor (NR)-mediated gene activation. During hormone-mediated geneactivation, NRs bind to the hormone and are activated. The activated NRs, along with various coregulators, bind to the hormone responseelements present in the promoters of hormone-responsive genes leading to their gene activation. Usually proteins containing an LXXLLdomain interact with NRs and act as coregulators for NR-mediated gene activation. MLLs (MLL1–4) contain one or more LXXLL domains.Therefore, MLLs may interact directly with NRs via their own LXXLL domain(s) and regulate NR-mediated gene activation. Alternatively,MLLs might interact with NRs via different MLL-interacting proteins such as ASC2, Menin, INI1 that contain multiple LXXLL domains. Inaddition to NR, there are various other NR coregulators (other than MLL and ASCOM) that, in coordination with NRs, have essential roles inNR-mediated gene activation. However, it is not yet clear if MLLs interact and ⁄ or coordinate with any of these NR coregulators (CBP ⁄ P300,PCAF, SRC-1 family, etc.) in a ligand-dependent manner to regulate NR-target genes.K. I. Ansari and S. S. Mandal Biochemical functions of MLLFEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS 1797and ER [6]. ASC2 contains two LXXLL domainsthrough which it interacts with NRs in a ligand-depen-dent manner. ASC2 is present in a steady-state multi-protein complex, ASCOM, that also contains variousother proteins including MLL histone methylases andMLL-interacting proteins Rbbp5, Wdr5 [6,73]. Morerecent studies identified additional ASCOM-specificcomponents that include PTIP, PTIP-associated pro-tein-1 and UTX (a H3K27-specific demethylase) [74].Thus, ASCOM contains two distinct groups of histonemodifier that are linked to transcriptional activation[73,75] and ASC2 bridges nuclear receptors and thesehistone modifiers [6,32,76].During retinoic acid-induced activation of RAR-2(a RAR target gene), ASC2 is recruited to the RAR-2promoter via interaction with RAR. Along withASC2, other ASCOM components including MLLs(MLL3 and MLL4) are recruited to the RAR-2 pro-moter and lead to H3K4 trimethylation, chromatinremodeling and gene activation in a retinoic acid-dependent manner. The presence of an intact LXXLLdomain is essential for ligand-dependent recruitment ofASC2 and other ASCOM components to the RAR-2promoter suggesting direct ligand-dependent interac-tion between ASC2 NR box (likely NR box 1) andRAR [6,75]. The NR box 1 of ASC2 also shows rela-tively weak yet specific interaction with the farne-soid X receptor during transactivation of FXR [32]. Bycontrast, in the case of LXR, the NR box 2 of ASC2specifically recognizes LXRs [6] and recruits MLL3and MLL4 to the LXR target gene, sterol regulatoryelement binding protein 1c (SREBP-1c). Mutation ofASC2 ablated the effect of LXR ligand (T1317) onLXR target gene expression by affecting H3K4 trime-thylation. However, mutation of MLL3 partiallysuppressed expression of the target genes [6].Lee et al. [75] demonstrated that independent knock-down of MLL3 and MLL4 results in attenuation ofretinoic acid-induced H3K4 trimethylation, but doesnot abolish it completely. However, parallel knock-down of both MLL3 and MLL4 suppresses retinoicacid-induced expression of RAR-b2 [75]. These obser-vations suggest that MLL3 and MLL4 are present inindependent ASCOM complexes and are redundant inhistone methylation [75]. This redundancy in theirfunction was further confirmed by depleting the com-mon subunits of ASCOM3 (containing MLL3) andASCOM4 (containing MLL4) complexes [75]. ThesiRNA-mediated depletion of Wdr5, Rbbp5 andAsh2L caused significant suppression of RAR-medi-ated H3K4 trimethylation of the RAR-b2 gene.Because both MLL3 and MLL4 in ASCOM complexesare recruited by NR box 1 of ASC2, depletion ofASC2 results in impaired recruitment of both MLL3and MLL4 affecting H3K4 trimethylation and RARtarget gene expression [75]. These results suggest thatthe key function of ASC2 in transactivation is to pres-ent MLL3 and MLL4 to the target gene promoter. Inaddition to acting as an anchor between NR andASCOM complexes, ASC2 also confers specificity ondifferent ASCOM complexes towards different hor-mone-induced genes [75]. For example, depletion ofMenin, a common component of MLL1 and MLL2,does not affect expression of RAR-2 in mouse embry-onic fibroblasts [75]. However, depletion of ASC2leads to not only impaired expression of RAR-2, butalso suppression of H3K4 trimethylation, indicatingthat RAR-2 is a specific target for MLL3 and MLL4but not for MLL1 and MLL2.Are MLLs involved in hormonal regulation ofHOX genes?Expression of the HOX genes is tightly regulatedthroughout development. Studies suggest thathormones play critical roles in the regulation of devel-opmental genes, including HOX. For example, retinoicacids affect Hox gene expression markedly and pro-duce homeotic transformation [77]. Retinoic acid regu-lates expression of 3¢ Hox paralogs including Hoxa1and Hoxb1 during development of the central nervoussystem in early embryogenesis. The well-definedboundaries of different sections of the brain are devel-oped by endocrine regulation of developmental geneexpression, including selected Hox genes [78].Although, retinoids regulate anterior Hox genes, recentdata showed that posterior Hox genes are regulated byestrogens and progesterone [79]. Neonatal exposure todiethylstilbestrol downregulated uterine Hoxa10expression [80]. Hoxb13, which is associated with thenormal differentiation and secretary function of themouse ventral prostate, is suppressed upon exposure toneonatal estrogen [81]. Ovariectomy in mouse affectsthe expression of Hoxc6, which is critical for mam-mary gland development and milk production [82].Expression of Hoxa10 in canine glandular epithelium,embryo, luminal epithelium and uterus fluctuates overdifferent stages of pregnancy, whereas Hoxa10 issignificantly upregulated by either estrogen or proges-terone. Similar to retinoic acid, estrogens regulateexpression of the 5¢ Hox paralogs such as Hoxa9,Hoxa10 and Hoxa11, which are expressed in posteriorand distal domains of the body axis [83]. Although thehormonal regulation of several HOX genes is drivenby developmental processes and MLLs are well knownas key regulators of HOX genes, the roles of MLLs inBiochemical functions of MLL K. I. Ansari and S. S. Mandal1798 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBShormonal regulation of HOX genes are largelyunknown.In an effort to understand the mechanism of HOXgene regulation, especially under hormonal environ-ments, we found that several HOX genes includingHOXC10 and HOXC13 are transcriptionally regulatedby estrogen [84]. Hoxc13 is a critical gene involved inthe regulation of hair keratin gene cluster and alope-cia, and Hoxc13-mutant mice lack external hair, sug-gesting a critical role in hair development [85].Although, steroid hormones are critical players in sex-ual differentiation and both HOXC13 and steroid hor-mones are linked with hair follicle growth anddifference in hair patterning in males and females, theroles of steroid hormones in HOXC13 gene regulationare unknown [86]. Our studies demonstrate thatHOXC13 is transcriptionally activated by estrogen(E2). HOXC13 promoter contains several estrogenresponse elements and ERs bind to these in anE2-dependent manner [84]. Knockdown of estrogenreceptors, ERa and ERb, suppresses E2-mediated acti-vation of HOXC13. Similarly, knockdown of histonemethylase MLL3 suppressed E2-induced activation ofHOXC13 [84]. MLL histone methylases (MLL1–4)were bound to the promoter of HOXC13 in anE2-dependent manner [84]. Furthermore, knockdownof either ERa or ERb affected the E2-dependent bind-ing of MLLs (MLL1-4) into HOXC13 estrogenresponse elements, suggesting critical roles for ERs inrecruiting MLLs into the HOXC13 promoter [84].Although further investigations are needed to under-stand the detailed mechanism of MLL-mediatedHOXC13 and other HOX genes regulation, thesestudies demonstrate that MLL histone methylases, incoordination with nuclear hormone receptors, do playcritical roles in the regulation of steroid hormone-mediated HOX genes and this mechanism of hormonalregulation of HOX genes may be linked with HOXgene regulation during development and diseases.Do MLLs have any roles in mRNAprocessing?In eukaryotes, gene expression involves various stepssuch as transcription (synthesis of RNA), mRNAprocessing (such as mRNA capping, splicing, poly-adenylation and cleavage), surveillance and export ofthe matured mRNA from the nucleus to the cytoplasmfor translation [1]. Diverse studies involving geneticand mutational analysis demonstrate that transcriptionis tightly coupled with mRNA processing [87].RNAPII is the key player in coordinating these co-transcriptional events via orchestrated recruitment oftranscription and mRNA-processing factors through-out transcription. Although an emerging view is thatall the steps from transcription, mRNA processing andtranslation are mechanically and functionally coupled,the proteins involved in this coupled process are stillpoorly characterized [87].MLLs are primarily recognized as having criticalroles in gene activation via H3K4 methylation of pro-moters. H3K4 trimethyl mark is thought to recruitvarious transcriptional coregulators during transcrip-tion activation. Trimethylation of histone H3 atlysine 4 localizes primarily at the 5¢ region of genesand is tightly associated with active loci. Recently,Reinberg and colleagues demonstrated that H3K4-trimethylated polypeptide specifically binds CHD1, achromatin remodeling factor involved in transcriptionelongation [88]. Using a conventional biochemicalpurification approach, they demonstrated that CHD1exists as a stable complex with components of thespliceosome. Knockdown of CHD1 by siRNA reducedthe association of U2 snRNP components with chro-matin, affecting the efficiency of pre-mRNA splicingon active genes in vivo [88]. Studies in yeast, Drosophilaand mammalian systems also demonstrate a role forCHD1 in transcript elongation and termination. Thesestudies suggest that methylated H3K4 serves to facili-tate the competency of pre-mRNA maturation throughbridging spliceosomal components to H3K4-trimethylvia CHD1. In addition, MLL complexes are alsoshown to coordinate Ski-complex that are critical play-ers in mRNA splicing suggesting further link betweenMLLs with transcription and mRNA processing [89].In most eukaryotic genes, exons are separated byintrons, and introns need to be spliced out prior totranslation. Splicing is carried by a spliceosome thatconsists of 100–300 different proteins. Increasingamounts of evidence suggest that transcriptional stimuli,such as steroid hormones (i.e. androgens, progestins,estrogen) not only change the expression of their targetgenes by binding and modulating the activity of theirnuclear receptors (NRs), but also modulate alternativesplicing events for different genes [90]. For example, ste-roid hormone estrogen (E2) modulates the expression ofsplice variants of the genes encoding ERa, VGEF andOxytocin [90]. Given the complexity of steroid hormonesignaling, multiple modes of action may operate inmaking alternate splicing decisions. These include post-translational modification of splicing factors and pro-moter-dependent recruitment of splicing factors viatranscriptional coregulators. In fact, NR coregulatorsare shown to interact with spliceosome and couple tran-scription with alternative splicing [90]. Several proteincandidates have been linked with alternative splicingK. I. Ansari and S. S. Mandal Biochemical functions of MLLFEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS 1799[...]... MLL K I Ansari and S S Mandal decisions For example, ERa interacts with SF3a, p120 and other components of snRNPs, and controls E2-dependent alternate splicing of the E2-responsive gene, oxytocin [90] NRs also interact with the SR (serine- and arginine-rich proteins) family of splicing factors CAPER, a SR-like protein, interacts with ERa and the progesterone receptor and modulates the ligand-dependent... regulation and disease The high conservation and multiplicity of MLLs in higher eukaryotes indicate that they have crucial and distinct roles in gene activation and other cellular events Although the discovery of MLLs and characterization of their HMT activities and protein–protein interaction profiles have shed significant light on their mechanism of action in gene activation, their detail functions in the... development and diverse types of human disease, including cancer and cardiovascular diseases, MLLs are likely linked with all those key physiological events and human diseases beyond their well-recognized roles in HOX gene regulation and mixed lineage leukemia Acknowledgements We thank Imran Hussain, Sahba Kasiri, Bishakha Shrestha, Saoni Mandal and other Mandal lab members for useful discussion and critical... LXXLL domain in different MLLs makes them attractive candidates for interaction with nuclear hormone receptors and associated gene regulation Even though studies demonstrate that MLLs are critical players in diverse types of NR-mediated gene regulation, their critical roles and interplay with different NR coregulators remain largely unexplored Because steroid hormones and nuclear receptors are intimately... H3K36 dimethylation during transcription initiation and elongation phases respectively EFs represent elongation factors 1800 FEBS Journal 277 (2010) 1790–1804 ª 2010 The Authors Journal compilation ª 2010 FEBS K I Ansari and S S Mandal indirectly, and we hypothesize that MLLs are potential key players in mRNA processing, their functional details in mRNA- processing events remain to be elucidated The... domain at the transcription imitation and elongation phases, respectively As some of the coregulators are specific to activated transcription (especially in presence of hormones or other stimuli), splicing and alternative splicing decisions (hence recruitment of SFs into the pre-initiation complexes) may be linked with hormone signaling Red and green methyl groups represent H3K4 trimethylation and H3K36... splicing [92] Because diverse studies demonstrate that MLL histone methylases (especially MLL2, MLL3 and MLL4) interact with NRs via critical involvement of ASCOM complexes that interact with factors involved in alternative splicing, it is likely that MLLs also coordinate the process of alternative splicing especially in hormoneregulated genes Conclusion MLL histone methylases are critical players in gene. .. the regulation of different types of genes are yet to be revealed In general, MLLs appear to have much wider roles in regulating gene activation beyond their HMT activities MLLs are master players in both basal and activated transcription, especially under an hormonal environment Although MLLs are found to interact with various mRNA- processing factors directly or Pre-initiation phase Elongation phase... initiation forming pretranscription initiation complexes (containing RNAPII, general transcription factors, mRNA capping enzymes, regulators and coregulators) Once the RNAPII moves to the transcription elongation phase, these SFs move onto the splice sites of the nascent pre -mRNA to execute splicing in a co-transcriptional manner S5-P and S2-P denote the phosphorylation states of the RNAPII C-terminal... Transcription linked to recombination: a gene- internal promoter coincides with the recombination hot spot II of the human MLL gene Oncogene 26, 1361–1371 Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM et al (2009) Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation . MINIREVIEW Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing Khairul I. Ansari and Subhrangsu S. MandalDepartment. a DNA-binding domain, a ligand-bindingdomain and a transactivation domain. The DNA-bind-ing domain is responsible for DNA binding specificity and dimerization,
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