COMMENTARY TAF4 takes flight Michael T. Marr II1 Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454 he eukaryotic mRNA transcrip- from yeast to man, but the region of ETO-TAFH domain was required for tion machinery is exceedingly conservation is limited to a histone H2A activation of the wingless target gene complex, perhaps reflecting the homology region at the carboxyl termi- naked cuticle (nkd) both in cultured requirement for response to nus of the protein (Fig. 1A). The meta- cells and in larval imaginal discs. They Tdiverse environmental and developmen- zoan homologues of TAF4 contain an further showed that this domain directly tal signals. Some of the machinery is extended amino terminus with two addi- interacts with the amino terminus of the common to all mRNA genes and in- tional conserved regions: a glutamine- pygopus, a dedicated transcription factor cludes RNA polymerase II (Pol II) and rich region and a more recently defined for wingless signaling. Interestingly, the a set of general transcription factors ETO-TAFH domain. amino terminus of pygopus has previ- (GTFs) (1). Signal-specific gene expres- The glutamine-rich region was one of ously been defined as absolutely neces- sion patterns are defined by sequence- the first coactivator domains of TFIID sary for Wg/Wnt signaling (14). These specific DNA-binding proteins (activa- to be defined (8). It interacts with a findings place TAF4 at the end of a tors) that bind cognate sites in the number of activators including Sp1 and chain of protein–protein interactions promoter and enhancers of target genes. CREB (8, 9). Additionally, disruption of that are required for activation of Wg/ In most cases activators are not suffi- such essential activator–coactivator in- Wnt signaling target genes (Fig. 1B). cient for stimulation of transcription. teractions in the glutamine rich region This work further cements TFIID as Instead, these DNA-binding proteins initiate the ordered assembly of large an important target of transcriptional multiprotein complexes (the coactiva- This work further activators. Moreover, these studies tors), in addition to the general factors, show that TAF4 itself contains at least at the promoters of target genes (2). A cements TFIID as an 3 different functional domains. The cursory examination of the complexes amino terminus may allow multiple involved in signal-responsive activated important target of contacts with TFIID through the com- transcription in a chromatin environ- binatorial action of multiple activators: ment indicates that Ͼ100 different transcriptional each interacts with either the polypeptides are involved in the process. glutamine-rich region or the ETO do- Many of these proteins occur in stable activators. main. In contrast, the histone fold do- multiprotein complexes. One of the cen- main plays an essential structural role tral players in this process is TFIID. in TFIID stability. TFIID consists of the TATA-binding of TAF4 plays a role in the progression Because TAF4 is a well-known target protein (TBP) and 12–13 TBP- of Huntington’s disease (10). of activators, it is not surprising to un- associated factors (TAFs) (3). TFIID The ETO-TAFH domain was origi- cover a coactivator function. The thought- forms the heart of the preinitiation nally defined based on sequence similar- provoking finding is that the region complex and DNA-binding proteins di- ity with the 8;21 (ETO) family of pro- defined for Wg/Wnt responsiveness, a rectly contact TFIID to stimulate the teins (11). Its structure has been solved metazoan-specific pathway, maps to a rate of transcription of target genes. An and it forms a compact 5-helix ‘‘wedge’’ metazoan-specific region of TAF4. The important remaining question in this with a binding pocket for hydrophobic fact that the other coactivator region of field is to uncover how each individual peptides (12). Although this domain can TAF4 (the glutamine-rich region, in- polypeptide contributes to gene activa- interact with a number of transcription volved in response to metazoan-specific tion within the context of the entire factor in vitro, no clear in vivo role for activators like Sp1) also maps to the complex. Experiments designed to test the ETO domain has been defined. amino terminus suggests that metazoans this are complicated because loss of one To investigate the role of TAF4 in a have expanded the TAF components critical subunit of a complex often leads physiological response, Wright and Tjian of TFIID to help interpret diverse to disintegration of the entire complex used the Wingless/Wnt (Wg/Wnt) signal- metazoan-specific signals. In their cur- (4–6). In a recent issue of PNAS, ing pathway (7). Wg/Wnt signaling plays rent article, together with their previous Wright and Tjian circumvent this prob- important roles in cell fate determina- lem and manage to dissect the role of a tion during animal development and has work, Wright and Tjian have been able single TFIID subunit, TAF4 in the con- also been implicated in control of adult to separate the structural requirements text of an otherwise intact holo-TFIID stem cell proliferation. Importantly, of TAF4 from the coactivator function complex (7). They identify a single there are a number of well-defined of TAF4 and they find that the more metazoan-specific domain of TAF4 that wingless targets in Drosophila. The Tjian ancient region of TAF4 (the histone is important for activation of wingless group had previously shown that the fold) is required for structural integrity (Wg/Wnt) target genes in Drosophila. carboxy-terminal histone fold is required and the newer region of TAF4 has ac- The work not only defines an in vivo for holo-TFIID complex formation, con- quired coactivator function (6, 7). role for this domain but also sets the sistent with work on human TAF4 A second important observation is the groundwork for the utilization of novel (6, 13). Building on this knowledge, they finding that TFIID and Pol II are pre- methods to dissect the function of engineered modified versions of TAF4 individual subunits of large protein that lacked regions of the amino termi- assemblies. nus. Importantly, all of these modified Author contributions: M.T.M. wrote the paper. TAF4 is considered a core subunit TAF4 proteins can still incorporate into The author declares no conflict of interest. because it is required for the integrity of the TFIID complex. This strategy al- See companion article on page 55 in issue 1 of volume 106. the holo-TFIID complex. It is conserved lowed them to show that the TAF4 1E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0812990106 PNAS ͉ February 3, 2009 ͉ vol. 106 ͉ no. 5 ͉ 1295–1296 Downloaded by guest on September 30, 2021 A N Q-rich ETO H2A C Metazoan TAF4 NCH2A Yeast TAF4 B Arm/β-catenin TCF/Pan lgs/BCL9 Q Pygo ETO TFIIDD TAF4 Pol II & GTFs TBP Fig. 1. Role of TAF4 in activation of wingless target genes. (A) Domain structure of TAF4. All TAF4 homologues contain a sequence similarity to histone H2A (H2A) at their carboxyl terminus. Only the metazoan TAF4 homologues contain an extended amino terminus. The amino terminus contains 2 regions that are targeted by transcription regulators. A glutamine-rich region close to the amino terminus (Q-rich) and an ETO-TAFH (ETO) domain in the middle of the protein. (B) Wingless/Wnt target genes are under the control of the TCF/pangolin (TCF/Pan) family of DNA-binding proteins. When the pathway is active, Armadillo/␤- Catenin (Arm/␤-Catenin) is stabilized and moves to the nucleus where it finds target genes by interacting with TCF/Pan. Legless/BCL9 (lgs/BCL9) and pygopus (Pygo) bridge the DNA-binding protein TCF to the basal machinery through interaction with TAF4 ETO domain. loaded and paused on the inactive nkd Wg/Wnt target genes, a novel function tions about TFIID function in transcrip- gene. Stimulation of the pathway leads for TFIID. tion activation. Is the TAF4 pygopus to only a slight increase in TFIID and Going forward, this work lays out an interaction required for setting up the pre- Pol II promoter occupancy but a great experimental plan to look at individual loaded polymerase or in allowing poly- increase in mRNA synthesis. This is im- subunits in larger complexes. By first map- merase escape? If RNA polymerase is portant in the light of new genomic ping the regions required for integrity of present with TFIID at the promoter, what analyses that show Pol II may be pre- the complex, and then investigating the is the mechanism of RNA polymerase loaded at a significant portion of the functional role of other domains, it is pos- release? It is also clear that TAF1 plays a genome (15–17). Thus, the TAF4- sible to identify small domains required role in wingless signaling, but what role? pygopus contact might play a role in for function in megadalton-size complexes. Further experiments will be needed to releasing paused polymerases from This work also raises several new ques- address these issues. 1. Thomas MC, Chiang CM (2006) The general transcrip- scription from a TATA-less promoter Proc Natl Acad Sci coactivator TAF4 binds to a short hydrophobic motif tion machinery and general cofactors. Crit Rev Biochem USA 103:12347–12352. present in transcriptional regulators. Proc Natl Acad Sci Mol Biol 41:105–178. 7. Wright KJ, Tjian R (2008) Wnt signaling targets ETO USA 104:7839–7844. 2. Taatjes DJ, Marr MT, Tjian R (2004) Regulatory diversity coactivation domain of TAF4/TFIID in vivo. Proc Natl 13. Furukawa T, Tanese N (2000) Assembly of partial TFIID among metazoan co-activator complexes Nat Rev. Mol Acad Sci USA 106:55–60.