Localization of transcription factor

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Expression patterns and immunohistochemical localization of PITX2B transcription factor in the developing mouse heart

Expression patterns and immunohistochemical localization of PITX2B transcription factor in the developing mouse heart

Expression patterns and immunohistochemical localization of PITX2B transcription factor in the developing mouse heart FRANCISCO HERNANDEZ TORRES*, DIEGO FRANCO, AMELIA E ARANEGA and FRANCISCO NAVARRO*[.]

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A Highly Organized Structure Mediating Nuclear Localization of a Myb2 Transcription Factor in the Protozoan Parasite Trichomonas vaginalis

A Highly Organized Structure Mediating Nuclear Localization of a Myb2 Transcription Factor in the Protozoan Parasite Trichomonas vaginalis

Nuclear proteins usually contain specific peptide sequences, referred to as nuclear localization signals (NLSs), for nuclear import. These signals remain unexplored in the protozoan pathogen, Trichomonas vagi- nalis. The nuclear import of a Myb2 transcription factor was studied here using immunodetection of a hemagglutinin-tagged Myb2 overexpressed in the parasite. The tagged Myb2 was localized to the nucleus as punctate signals. With mutations of its polybasic sequences, 48KKQK51 and 61KR62, Myb2 was localized to the nucleus, but the signal was diffusive. When fused to a C-terminal non-nuclear protein, the Myb2 sequence spanning amino acid (aa) residues 48 to 143, which is embedded within the R2R3 DNA-binding domain (aa 40 to 156), was essential and sufficient for efficient nuclear import of a bacterial tetracycline repressor (TetR), and yet the transport efficiency was reduced with an additional fusion of a firefly luciferase to TetR, while classical NLSs from the simian virus 40 T-antigen had no function in this assay system. Myb2 nuclear import and DNA-binding activity were substantially perturbed with mutation of a conserved isoleucine (I74) in helix 2 to proline that altered secondary structure and ternary folding of the R2R3 domain. Disruption of DNA-binding activity alone by point mutation of a lysine residue, K51, preceding the structural domain had little effect on Myb2 nuclear localization, suggesting that nuclear translocation of Myb2, which requires an ordered struc- tural domain, is independent of its DNA binding activity. These findings provide useful information for testing whether myriad Mybs in the parasite use a common module to regulate nuclear import.
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Multiple Nuclear Localization Signals Mediate Nuclear Localization of the GATA Transcription Factor AreA

Multiple Nuclear Localization Signals Mediate Nuclear Localization of the GATA Transcription Factor AreA

AreA is unusual in the large number of NLSs it contains. Nu- clear localization signals in other transcription factors are quite variable in both type and number. For many transcription factors, a single NLS mediates nuclear import. For example, A. nidulans PrnA, the constitutively nuclear transcriptional activator for pro- line utilization pathway genes, has a tripartite NLS located in its N-terminal region (15). A single NLS is also found in other A. nidulans transcription factors: AlcR, NirA and AmyR each have a tripartite NLS (16, 17, 31), and VeA and PacC have a classical bipartite NLS (32, 90, 91). There are many examples of nuclear proteins containing multiple NLSs; however, there are usually no more than three (24, 26). A. nidulans HapB has two monopartite NLSs located in the C-terminal domain (18, 19). One of these NLSs is conserved in fungal, yeast, and human HapB orthologs, and is functional in A. nidulans HapB, S. cerevisiae Hap2p, and human NF-YA proteins expressed in S. cerevisiae (19). The other NLS is found only in the aspergilli, but it is required for nuclear localization of HapB in A. nidulans (19). Both NLSs are functional in Aspergillus oryzae HapB (92). The AreA NLSs show apparent redundancy in their ability to promote localization of AreA and GFP to the nucleus. If these sequences share truly redundant func- tions, we might expect them to be lost over time in different lin- eages. However, all of the NLSs are conserved across most fungal species, suggesting that each NLS has an important and unique function. One possibility is that AreA may use alternative import- ins for nuclear import under different growth conditions due to differential expression of importins. A. nidulans has 17 nuclear importins, but the expression of these across different growth con- ditions has not been determined (12). Alternatively, multiple NLSs could allow for more-efficient nuclear import. The cooper- ativity we observed for the AreA classical NLSs suggests low bind- ing affinities of individual NLSs to nuclear importin(s). ␣-Impor- tin binds to different NLSs, including classical NLSs, via either of two NLS-binding grooves (93). Binding of multiple AreA NLSs to different binding grooves of importin(s) may confer stronger binding affinity and more-efficient nuclear import. The RRX
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Pou3f transcription factor expression during embryonic development highlights distinct pou3f3 and pou3f4 localization in the Xenopus laevis kidney

Pou3f transcription factor expression during embryonic development highlights distinct pou3f3 and pou3f4 localization in the Xenopus laevis kidney

POU-domain and the conservation of the variable linker region. The Pou3f class is composed of 4 intronless genes, pou3f1 (alternatively called oct6, otf6, pou50, scip, test1, tst1, nrl-22 or XLPOU1), pou3f2 (alternatively called BRN2, OCT7, OTF7, OTF-7, POUF3, brn-2, oct-7 or N-Oct3), pou3f3 (alternatively called BRN1, OTF8, oct-8 or brain-1), and pou3f4 (alternatively called BRAIN-4, BRN-4, BRN4, DFN3, DFNX2, OCT-9, OTF-9 or OTF9). They have been shown to be involved in neural and ectodermal development in mammals. Pou3f1 promotes neural fate commitment during mouse gastrulation (Zhu et al., 2014). It is implicated in Schwann cell myelinization and oligodendrocyte as well as keratinocyte differentiation (Zhao, 2013). Pou3f2 is a regulator of melanocyte growth and tumorigenesis. It is re- sponsive to MAPK pathway activation and modulates the levels of the transcription factor MITF, hence preventing melanocytic differentiation ultimately leading to tumor metastasis (Cook and Sturm, 2008). Pou3f4 is implicated in neuron and otic vesicle development, where it controls cochlea formation. In humans, defects in POU3F4 cause X-linked deafness type 3 (Zhao, 2013). Pou3f transcription factors can act redundantly during embryonic development. In single Pou3f2 or Pou3f3 mouse mutants, no developmental defects are observable in the neocortex where these genes are co-expressed, while the double mutants of both Pou3f2 and Pou3f3 are characterized by abnormal formation of the neocortex with dramatically reduced production of layer II-IV neurons and defective migration of neurons (Cook and Sturm, 2008).
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Degradation of Saccharomyces cerevisiae Transcription Factor Gcn4 Requires a C-Terminal Nuclear Localization Signal in the Cyclin Pcl5

Degradation of Saccharomyces cerevisiae Transcription Factor Gcn4 Requires a C-Terminal Nuclear Localization Signal in the Cyclin Pcl5

Expression of the different Pcl5-GFP fusion proteins was verified by Western hybridization of S. cerevisiae cell extracts using monoclonal anti-GFP antibodies (data not shown). The functionality of all Pcl5-GFP hybrids was tested by their ability to suppress Gcn4 overexpression toxicity. High overexpression of GCN4 inhibits cellular growth, possibly by the interference of Gcn4 with other transcriptional activation pathways (55). A pcl5-deficient yeast strain is hypersensitive to even moderately overexpressed GCN4 fused to the GAL1 promoter (52). Whereas GFP by itself is unable to suppress overexpression toxicity of Gcn4 on solid medium, as well as in liquid culture, all Pcl5 fusions tested carrying either C-terminal (see Fig. 2B) or N-terminal GFP (data not shown) complemented the pcl5 mutant phenotype, indicating that the addition of GFP does not influence the localization of Pcl5 or interfere with kinase activation or substrate recognition. A GFP fusion of PCL5, integrated in a single copy at the original locus, is already sufficient to suppress Gcn4 toxicity (data not shown).
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Nac1 interacts with the POZ-domain transcription factor, Miz1.

Nac1 interacts with the POZ-domain transcription factor, Miz1.

The nucleus contains distinct nuclear bodies that compartment- alize the organelle to facilitate efficient biological processes (re- viewed in [58]). Several POZ-domain transcription factors and Cul3 adaptors are found in discrete nuclear structures that have variously been termed bodies or speckles [27], and the local- ization of these POZ proteins in nuclear bodies directs the co- localization of their interacting partners [23,59]. Nac1 is found in discrete bodies within the nucleus of normal and cancer cells [7]; although it has not been determined whether these structures play a role in transcriptional regulation or protein ubiquitination, it is conceivable that they could represent hubs that recruit and silence multiple specific gene loci in a manner similar to the repressive function of polycomb bodies (reviewed in [58]). In order to determine whether the subcellular localization of Miz1 is modulated by its interaction with Nac1, we expressed fluor- escently tagged Miz1 and Nac1 proteins in HeLa cells. When expressed individually, mCherry-Nac1 2 − 794 (mCherry-tagged
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Activated transcription factor nuclear factor kappa B is present in the atherosclerotic lesion

Activated transcription factor nuclear factor kappa B is present in the atherosclerotic lesion

Immunohistochemistry. An immunohistochemical procedure for sequential double antigen localization was applied with minor modifi- cations (39). The frozen sections were thawed, and the tissue was fixed in 3.7% buffered formaldehyde (5 min) followed by acetone (50, 100, and 50%; 2 min each). Then, sections were rehydrated in 0.1 M PBS for 5 min, and unspecific binding was blocked with 1% BSA. Incubation with the primary antibody was performed overnight at 4 8 C. The sections were washed twice in 0.1 M PBS and incubated with the biotinylated secondary antibody (Dianova) at room temperature for 1 h. After washing, the tissue was incubated with the streptavidin biotin peroxidase complex (Zymed Laboratories, Inc., San Francisco, CA) at room temperature for 1 h, washed again, and incubated in 0.03% wt/vol 3-3 9 diaminobenzidine (DAB) (Sigma Chemical Co.) with 0.003% vol/vol hydrogen peroxide until a brown reaction prod- uct could be seen. To suppress any remaining peroxidase, the slides were incubated in 3% hydrogen peroxide for 30 min. After washing three times, the sections were incubated with the second incubation
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Regulation of the Ets transcription factor Tel

Regulation of the Ets transcription factor Tel

(Fig 3b). CtBP1 and CtBP2 share a high degree of sequence homology (80% identity; 91% overall similarity), but differ completely in the composition of their N-termini (composed of fourteen amino acids and twenty amino-acids respectively). Our mutational analysis of CtBP2 suggests that the substantially higher binding of CtBP2 to Tel is mediated by the positively charged residues in this region (that are absent in CtBP1). These residues could selectively reinforce binding to Tel through ionic interactions with the negatively charged amino acids abutting the Tel PxEIM motif. Fig 3c shows that the N-terminus of CtBP2 (but not CtBP1) is positively charged due to three arginine residues (and a histidine residue) together with three lysine residues (K6, K8 and K10) that are known substrates of acetylation and which are required for correct CtBP2 subcellular localization (via acetylation of K10) 78 . We found that mutation of these residues had no effect on the interaction between Tel and CtBP2 so long as the positive charge was preserved, whereas loss of the charge abrogated the interaction (Fig 3c). As expected 78 , mutation of these residues to either arginine or alanine resulted in mislocalization of CtBP2 (data not shown). In light of these findings, it is noteworthy that knock-out studies in mice revealed that whereas mice lacking CtBP1 are viable and fertile (although 30% smaller), loss of CtBP2 leads to embryonic lethality 71 . This implies that some CtBP2 functions are non-redundant and our evidence suggests that regulation of Tel could be one such case. Overall, these data show that Tel harbours a bona fide CtBP-binding site through which it binds to CtBP1 and CtBP2 but to CtBP2 with substantially higher efficiency.
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The transcription factor SOX30 is a key regulator of mouse spermiogenesis

The transcription factor SOX30 is a key regulator of mouse spermiogenesis

One interesting observation in Sox30 KO mice is that STs with multiple chromocenters are significantly more frequent than in wild-type mice. As chromocenters are foci of aggregated pericentric heterochromatins and are organizing centers of high order chromatin structures, this phenotype suggests that Sox30 may play a role, either directly or indirectly, in the global chromatin re- modeling that occurs during spermiogenesis. The single ST chromocenter is reported to be formed immediately after the second meiotic division (Hoyer-Fender et al., 2000). Therefore, the regulation of chromocenter formation by SOX30 is most likely a direct role of SOX30 and/or its regulated genes, rather than a reflection of arrested differentiation. The KO of a number of genes (Trf2, Hmgb2, Brdt and Seipin) also results in the same multiple chromocenter phenotype (Berkovits and Wolgemuth, 2011; Catena et al., 2006; El Zowalaty et al., 2015; Martianov et al., 2002). However, we found that none of these genes was regulated by SOX30. Therefore, either SOX30 directly regulates chromocenter formation or other mediators have yet to be identified. Noncoding RNAs have recently been reported to be involved in heterochromatin formation (Nishibuchi and Dejardin, 2017). We also tried to identify genomic features, such as localization to pericentric regions or enrichment of retrotransposons, of the SOX30-regulated genes, including lncRNA genes, but unfortunately no significant candidates with these properties were identified.
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Therapeutic applications of transcription factor decoy oligonucleotides

Therapeutic applications of transcription factor decoy oligonucleotides

under control of a single transcription factor represent important limitations to the decoy ODN strategy. Speci- ficity becomes an even greater challenge when target gene expression is to be inhibited only in a single organ or tissue type, since systemic delivery of the DNA is like- ly to lead to widespread uptake and potential nonspe- cific side effects. In addition, as with other ODN strate- gies, the successful use of transcription factor decoys will almost always depend on an efficient means to deliver the synthetic DNA to target cells. Although one recent report describes a mechanism by which decoy binding in the cytoplasm prevents nuclear translocation of NF-κB (31), for most applications, decoy ODNs are thought to require nuclear localization if they are to prevent the transactivation of their target genes. Unfortunately, the endocytotic pathways for phosphorothioate and other ODN uptake translocates most of the ODN into lysoso- mal compartments, where it is degraded.
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Transcription factor mutations as a cause of familial myeloid neoplasms

Transcription factor mutations as a cause of familial myeloid neoplasms

events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.
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Spliced Leader RNA Gene Transcription in Trypanosoma brucei Requires Transcription Factor TFIIH

Spliced Leader RNA Gene Transcription in Trypanosoma brucei Requires Transcription Factor TFIIH

glycoprotein and procyclin (10). Although all class I promoters function in the in vitro system, the GPEET procyclin gene promoter is most effective (19). Hence, we cotranscribed the templates GPEET-trm and SLins19, which harbor the GPEET gene/promoter and SL RNA gene promoter, respectively. Both templates carry unrelated tag sequences downstream of the transcription initiation site, enabling the specific detection of the GPEET-trm and SLins19 RNAs by primer extension as- says. To assess the function of XPD for SL RNA gene tran- scription, we first prepared transcription extract from TbX1 cells which exclusively express XPD-PTP. Subsequently, we depleted XPD from this extract by IgG chromatography (Fig. 7A). In comparison to mock-treated extract, XPD depletion virtually abolished transcription of template SLins19, whereas it did not affect GPEET-trm transcription (Fig. 7B). The tran- scriptional activity of SLins19 could be partially restored in a dose-dependent manner when the final peptide eluate of the XPD-PTP tandem affinity purification was added back (Fig. 7B, ⫹ Elu). This was not a nonspecific effect of the tag, because we have previously shown that PTP-tagged TbSNAP2 and TbRPA1 proteins are unable to stimulate SL RNA gene tran- scription in TFIIB-depleted extract (29). Hence, these results demonstrated that the observed effects on SL RNA gene tran- scription were caused by the XPD-PTP purified proteins. They did not, however, unambiguously identify XPD as an essential protein for this activity. To show this, we prepared transcrip- tion extract from an XPD-RNAi competent cell line before and 72 h after inducing synthesis of XPD dsRNA. In compar- ison to the previous experiments, the relative activities of GPEET-trm and SLins19 transcription were different (Fig. 7B and C). This variability was most likely a result of large- and small-scale extract preparations for the depletion and RNAi experiments, respectively. Nevertheless, the signal strengths within each experimental set were consistent. Hence, the re- sults clearly showed that SLins19 transcription was strongly affected by XPD silencing, whereas GPEET-trm transcription was not (Fig. 7C). Since the final peptide XPD-PTP eluate fully reconstituted the transcriptional activity, again in a dose-de- pendent manner, a nonspecific RNAi effect could be excluded. Thus, we concluded that XPD is essential for SL RNA gene transcription in T. brucei.
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A transcription factor contributes to pathogenesis and virulence in Streptococcus pneumoniae

A transcription factor contributes to pathogenesis and virulence in Streptococcus pneumoniae

A comprehensive view of bacterial functional genomics can be obtained by categorizing up-regulated/down-regulated genes into a limited number of annotated GO groups. GO classification has been well developed for eukaryotes; however, it has not been extensively applied in understanding functional genomics of bacteria. Here, we assigned GO groups to up-regulated and down-regulated pneumococcal genes in both WCH16 and WCH43 using our recently developed comparative GO web application [20]. Specific attention was paid to GO classes involved in regulatory mechanisms such as sequence-specific DNA binding transcription factors, DNA binding, and two- component response regulator activity. We used this classification for increasing the quality of gene selection. More importantly, GO classification increased our knowledge about bacterial functional genome arrangement and shift during infection of different host tissues. GO categories were classified as: biological process, cellular component, and molecular function.
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Phosphorylation and dimerisation of transcription factor ATF-1

Phosphorylation and dimerisation of transcription factor ATF-1

understanding of how Q-rich domains function may provide more specific insight into the mechanisms of activation by CREB. To date, the best characterised Q-rich domains are found in ubiquitous activators such as Spl (Gourey and Tjian, 1988), Octi (Tanaka and Herr, 1990) and in the NF-YA subunit of the CGAAT box binding protein NFY (Li et a/., 1992). A recent study suggests that these Q-rich domains are 'proximal' activation domains. The abilities of several different activation domains to activate transcription when bound either to remote remote enhancer sites or to proximal promoter sites was tested (Seipel et ai, 1992). Q-rich domains were unable to stimulate transcription from a remote site and proline-rich sequences only weakly. In contrast, acidic and serine/threonine-rich domains were potent long-range activators (Seipel et ai, 1992). This indicates that activation from a distance may involve a fundamentally different mechanism to that of proximal activation and therefore implies that Q-rich domains may activate by only one mechanism (i.e. direct interaction with the general transcription factors). Downstream targets for Q-rich domains are beginning to be identified. For example, the Q-rich domain of the D. melanogaster fushi tarazu protein appears to interact directly with TFIIB (Golgan et ai, 1993). In addition, the D. melanogaster coactivator protein, TAF110 has been demonstrated to interact specifically with the Q-rich domains of Spl (Hoey et ai, 1993). This suggests that TAF110 may function as a mediator between activators with Q-rich domains (like Spl) and the TFIID complex.
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Transcription factor interplay during Drosophila haematopoiesis

Transcription factor interplay during Drosophila haematopoiesis

That is the case notably for those controlling the first steps of lymph gland specification and regionalisation. Lymph gland pre- cursors are specified in the lateral mesoderm during mid-embryo- genesis. The TALE-class homeodomain transcription factor Homothorax (Hth) is initially expressed ubiquitously in the lymph gland but its expression is subsequently downregulated in the posterior cells as they start to express the HOX factor Antennapedia (Antp) and Collier (Col), the orthologue of mammalian Early B-cell Factor (EBF) (Crozatier et al. 2004; Mandal et al. 2007). These posterior cells prefigure the Posterior Signalling Center (PSC), which plays a key role in maintaining the cells of the medullary zone into a progenitor state in the larval lymph gland (Krzemien et al. 2007; Mandal et al. 2007). col is required for PSC cells identity and thus for progenitor blood cell maintenance (Crozatier et al. 2004; Krzemien et al. 2007; Mandal et al. 2007). Its initial expression in the PSC precursors requires antp (Mandal et al. 2007), while its maintenance requires Serrate/Notch signalling (Krzemien et al. 2007). It was proposed that Antp and Hth cross inhibit each other to specify the PSC and the rest of the lymph gland, respectively (Mandal et al. 2007), but the molecular basis for this antagonism remains to be explored. In mammals, Meis1, the homologue of Hth, is also required for definitive haematopoiesis (Hisa et al. 2004; Azcoitia et al. 2005) and it plays a crucial role in leukaemogenesis, notably as a cofactor for Hoxa9 (Zeisig et al. 2004; Wong et al. 2007).
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Characterisation of a cellular transcription factor which co-ordinates cell cycle events with transcription

Characterisation of a cellular transcription factor which co-ordinates cell cycle events with transcription

Much work has centred on the control of viral promoters in embryonic stem (ES) cells and in the F9 embryonal carcinoma (EC) cell line as a means for defining cellular transcription factors regulated during differentiation. F9 EC cells are pluripotential stem cells derived from an explanted teratocarcinoma (Bemstine et a/., 1973). They can be induced to differentiate using, cAMP and retinoic acid (RA), to form several cell types similar to those in the developing mouse embryo. Treatment with RA gives rise to primitive endoderm whereas cAMP and retinoic acid together produce parietal endoderm (Strickland and Mahdavi, 1978;Strickland et a/., 1980). Some viral promoters are inefficiently transcribed in EC cells which could result from a lack of positively acting factors or from the presence of specific repressors, though it is possible that both models are applicable. For example the SV40 and polyoma virus enhancers are poorly transcribed in EC cells but more efficiently in PE cells. This in part can be explained by the cellular transcription factor PEAl (murine AP-1) which regulates expression of the polyoma enhancer and is abundant in differentiated cells but low in EC cells (Kryske et a/., 1987).
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The Genetics of Transcription Factor DNA Binding Variation

The Genetics of Transcription Factor DNA Binding Variation

Analysis of genomic variation in humans (Auton et al., 2015) as well as in model species such as the mouse (Keane et al., 2011; Yalcin et al., 2011) and fruit fly (Huang et al., 2014; Massou- ras et al., 2012) is providing unprecedented opportunities to understand the genetic basis of complex traits, including disease susceptibility. An important insight that emerged from genome- wide association studies (GWAS) is that the vast majority of significantly associated genetic variants is located in non-coding regions and may thus impact gene regulation. For example, of 465 unique trait/disease-associated single nucleotide polymor- phisms (SNPs) derived from 151 GWAS studies, only 12% are located in protein-coding regions, while 40% fall within introns and another 40% in intergenic regions (Hindorff et al., 2009). In addition, genome-wide profiling of accessible chromatin regions using DNase I hypersensitivity (DHS) mapping revealed that almost 60% of non-coding GWAS SNPs and other variants are located within DHS sites, with another 20% being in complete linkage disequilibrium (LD) with variants that lie in a proximate DHS site (Maurano et al., 2012). Since DHS sites reflect the oc- cupancy of DNA binding proteins such as transcription factors (TFs), these data indicate that GWAS loci may alter the binding of TFs and, as such, induce variation in gene expression and ultimately in complex organismal phenotypes. In this Review, we summarize the findings that led to this increasingly accepted notion of the importance of variation in TF-DNA binding in medi- ating phenotypic diversity. In addition, we strive to clarify why, for the majority of studied traits or diseases, establishing a mecha- nistic link between regulatory and phenotypic variation is still very challenging.
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Variable structure motifs for transcription factor binding sites

Variable structure motifs for transcription factor binding sites

Stat5a and Stat5b are members of the large family of Stat proteins. These more complex proteins form homo- dimers. A unit consists of an a helix bundle, a b barrel, an a helix connector region as well as an SH2 domain that forms the dimer interface. The b barrel and parts of the a helices interact with the DNA. It has been observed before that the Stat transcription factor is able to bind with different spacing between the motifs recog- nised by each unit of the dimer [66]. Presumably varia- tions in spacing can be comparatively easily accommodated by rearrangements of the SH2 interfaces. The POU region is part of several eukaryotic tran- scription factors. It consists of two DNA binding domains, a homeodomain and a POU specific domain. Both domains show no protein-protein contact and are
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Transcription factor ETV1 is essential for rapid conduction in the heart

Transcription factor ETV1 is essential for rapid conduction in the heart

This study identifies ETV1 as a critical factor essential for trans- ducing endocardially derived NRG1 signals into a transcriptional program responsible for fast conduction gene programming in the heart. ETV1 is a known target of ErbB2 and MAPK signaling path- ways and has been implicated in specification, patterning, and functional modulation of various cell types (37, 38, 40). In the gas- trointestinal tract, ETV1 is necessary both for proper development of myenteric and intramuscular interstitial cells of Cajal and for malignant transformation of these cell types into gastrointestinal stromal tumors (47). In the central nervous system, ETV1 has been shown to regulate terminal differentiation of cerebellar granule cells (39) and dopaminergic neurons (48). ETV1 has a direct role in establishing the sensory-motor circuitry in the developing spinal cord (38) and also dynamically modulates the electrophysiological properties of postmitotic fast-spiking interneurons through tran- scriptional regulation of K v 1.1 channels (37), the activity of which is also known to be regulated by NRG1/ErbB4 (49). Our data now implicate ETV1 as a major regulator of cardiac conduction biology and place it in the context of NRG1 signaling in the heart. Through NRG1-dependent activation of the Ras-MAPK pathway, ETV1 expression and activity are confined to subendocardial atrial and Purkinje myocytes, where ETV1 orchestrates the expression of the fast conduction gene program.
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Transcription factor haploinsufficiency: when half a loaf is not enough

Transcription factor haploinsufficiency: when half a loaf is not enough

Because transcription factors regu- late the expression of one or more downstream target genes, the finding that a mutation that reduces by 50% the level of these factors has any clin- ical effect is surprising for several rea- sons. First, studies of prokaryotic genes have suggested that gene tran- scription can be an all-or-none response. Second, neither cell-based assays nor in vitro analyses of mam- malian transcription factors usually indicate dramatic effects in response to twofold changes in levels of a tran- scription factor. Third, of the myriad genetically engineered mice pro- duced with haploinsufficiency of a given transcription factor (i.e., het- erozygous knockout mice), most het- erozygous mice are reported to have no demonstrable phenotype. As rec- ognized by Pohlenz et al. (2) and oth- ers (e.g., see ref. 6), the apparent absence of a phenotype might reflect nothing more than incomplete study, but it is also possible that reduced levels of certain factors (gata4, Irx4, fos, and myc among them) are truly inconsequential, at least in some genetic backgrounds.
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