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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A TAF4 coactivator function for E proteins that involves enhanced TFIID binding

ABSTRACT: The multisubunit TFIID plays a direct role in transcription initiation by binding to core promoter elements and directing preinitiation complex assembly. Although TFIID may also function as a coactivator through direct interactions with promoter-bound activators, mechanistic aspects of this poorly defined function remain unclear. Here biochemical studies show a direct TFIID-E protein interaction that (i) is mediated through interaction of a novel E protein activation domain (AD3) with the TAF homology (TAFH) domain of TAF4, (ii) is critical for activation of a natural target gene by an E protein and (iii) mechanistically, acts by enhancing TFIID binding to the core promoter. Complementary assays establish a gene-specific role for the TAFH domain in TFIID recruitment and gene activation in vivo. These results firmly establish TAF4 as a bona fide E protein coactivator, as well as a mechanism involving facilitated TFIID binding through direct interaction with an E protein activation domain. Genome-wide profiling of mRNA levels in MEF lines with Taf4 loxp/- (ctrl), Taf4 -/- (ko), Taf4 -/- Tg:hTAF4 wt, and Taf4 -/- Tg: hTAF4 ? (TAFH-deleted).

ORGANISM(S): Mus musculus

SUBMITTER: Huimin Geng

PROVIDER: E-GEOD-46807 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A TAF4 coactivator function for E proteins that involves enhanced TFIID binding

Project description:The multisubunit TFIID plays a direct role in transcription initiation by binding to core promoter elements and directing preinitiation complex assembly. Although TFIID may also function as a coactivator through direct interactions with promoter-bound activators, mechanistic aspects of this poorly defined function remain unclear. Here biochemical studies show a direct TFIID-E protein interaction that (i) is mediated through interaction of a novel E protein activation domain (AD3) with the TAF homology (TAFH) domain of TAF4, (ii) is critical for activation of a natural target gene by an E protein and (iii) mechanistically, acts by enhancing TFIID binding to the core promoter. Complementary assays establish a gene-specific role for the TAFH domain in TFIID recruitment and gene activation in vivo. These results firmly establish TAF4 as a bona fide E protein coactivator, as well as a mechanism involving facilitated TFIID binding through direct interaction with an E protein activation domain.

2013-06-06 | GSE46807 | GEO

TAF4 promotes pre-initiation complex formation and HNF4A occupancy of regulatory elements required to activation post-natal gene expression programme in hepatocytes (RNA-seq)

Project description:The nuclear receptor HNF4A regulates embryonic and post-natal hepatocyte gene expression. Using hepatocyte-specific inactivation in mice, we show that the TAF4 subunit of TFIID acts as a cofactor for HNF4A in vivo and that HNF4A interacts directly with the TAF4-TAF12 heterodimer in vitro. In vivo, TAF4 is required to maintain HNF4A-directed embryonic gene expression at post-natal stages and for HNF4A-directed activation of post-natal gene expression. TAF4 promotes HNF4A occupancy of functional cis-regulatory elements located adjacent to the transcription start sites of post-natal expressed genes and for pre-initiation complex formation required for their expression. Promoter-proximal HNF4A-TFIID interactions are therefore required for pre-initiation complex formation and stable HNF4A occupancy of regulatory elements as two concomitant mutually dependent processes. RNA profiles in wild-type and Taf4-/- livers by deep sequencing

2014-09-25 | E-GEOD-57712 | biostudies-arrayexpress

Gene expression changes associated with 3D growth of TAF4 knock out fibroblasts

Project description:Collagen 6A3 (Col6a3), a component of extracellular matrix, is often up-regulated in tumours and is believed to play a pro-oncogenic role. However the mechanisms of its tumorigenic activity are poorly understood. We show here that Col6a3 is highly expressed in densely growing mouse embryonic fibroblasts (MEFs). In MEFs where the TAF4 subunit of general transcription factor IID (TFIID) has been inactivated, elevated Col6a3 expression prevents contact inhibition promoting their 3 dimensional growth as foci and fibrospheres. Analyses of gene expression in densely growing Taf4-/- MEFs revealed repression of the Hippo pathway and activation of Wnt signalling. The Hippo activator Kibra/Wwc1 is repressed under dense conditions in Taf4-/- MEFs, leading to nuclear accumulation of the proliferation factor YAP1 in the cells forming 3D foci. At the same time, Wnt9a is activated and the Sfrp2 antagonist of Wnt signalling is repressed. Surprisingly, treatment of Taf4-/- MEFs with all-trans retinoic acid (ATRA) restores contact inhibition suppressing 3D growth. ATRA represses Col6a3 expression independently of TAF4 expression and Col6a3 silencing is sufficient to restore contact inhibition in Taf4-/- MEFs and to suppress 3D growth by reactivating Kibra expression to induce Hippo signalling and by inducing Sfrp2 expression to antagonize Wnt signalling. All together, these results reveal a critical role for Col6a3 in regulating both Hippo and Wnt signalling to promote 3D growth, and show that the TFIID subunit TAF4 is essential to restrain the growth promoting properties of Col6a3. Our data provide new insight into the role of extra cellular matrix components in regulating cell growth. 6 samples corresponding to non-confluent cells, confluent cells and cells growing as fibrospheres were analyzed. Each growing condition was done in duplicate.

2014-03-06 | E-GEOD-53098 | biostudies-arrayexpress

TAF4 promotes pre-initiation complex formation and HNF4A occupancy of regulatory elements required to activation post-natal gene expression programme in hepatocytes (ChIP-seq)

Project description:The nuclear receptor HNF4A regulates embryonic and post-natal hepatocyte gene expression. Using hepatocyte-specific inactivation in mice, we show that the TAF4 subunit of TFIID acts as a cofactor for HNF4A in vivo and that HNF4A interacts directly with the TAF4-TAF12 heterodimer in vitro. In vivo, TAF4 is required to maintain HNF4A-directed embryonic gene expression at post-natal stages and for HNF4A-directed activation of post-natal gene expression. TAF4 promotes HNF4A occupancy of functional cis-regulatory elements located adjacent to the transcription start sites of post-natal expressed genes and for pre-initiation complex formation required for their expression. Promoter-proximal HNF4A-TFIID interactions are therefore required for pre-initiation complex formation and stable HNF4A occupancy of regulatory elements as two concomitant mutually dependent processes. Examination of PIC, H3k4me3, Ctcf and Hnf4a occupancy in wild-type and Taf4-/- livers by deep sequencing

2014-09-25 | E-GEOD-57807 | biostudies-arrayexpress

A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (RNA-seq)

Project description:Targeting of general coactivators, such as BRD4, is an emerging strategy to interfere with oncogenic transcription factors (TFs) in cancer. However, coactivator perturbations have the potential to influence the function of numerous TFs, thereby resulting in biological pleiotropy. Here we identify TAF12, an 18 kilodalton subunit of TFIID/SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this AML-specific dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of a histone-fold domain fragment of TAF4 can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.

2018-01-08 | GSE104308 | GEO

A TFIID-SAGA perturbation that targets MYB and suppresses acute myeloid leukemia (ChIP-seq)

2018-01-08 | GSE104307 | GEO

TAF4 promotes pre-initiation complex formation and HNF4A occupancy of regulatory elements required to activation post-natal gene expression programme in hepatocytes (ChIP-seq)

2014-09-25 | GSE57807 | GEO

TAF4 promotes pre-initiation complex formation and HNF4A occupancy of regulatory elements required to activation post-natal gene expression programme in hepatocytes (RNA-seq)

2014-09-25 | GSE57712 | GEO

Retinoic acid induced changes in gene expression in TAF4 knock out fibroblasts

Project description:Collagen 6A3 (Col6a3), a component of extracellular matrix, is often up-regulated in tumours and is believed to play a pro-oncogenic role. However the mechanisms of its tumorigenic activity are poorly understood. We show here that Col6a3 is highly expressed in densely growing mouse embryonic fibroblasts (MEFs). In MEFs where the TAF4 subunit of general transcription factor IID (TFIID) has been inactivated, elevated Col6a3 expression prevents contact inhibition promoting their 3 dimensional growth as foci and fibrospheres. Analyses of gene expression in densely growing Taf4-/- MEFs revealed repression of the Hippo pathway and activation of Wnt signalling. The Hippo activator Kibra/Wwc1 is repressed under dense conditions in Taf4-/- MEFs, leading to nuclear accumulation of the proliferation factor YAP1 in the cells forming 3D foci. At the same time, Wnt9a is activated and the Sfrp2 antagonist of Wnt signalling is repressed. Surprisingly, treatment of Taf4-/- MEFs with all-trans retinoic acid (ATRA) restores contact inhibition suppressing 3D growth. ATRA represses Col6a3 expression independently of TAF4 expression and Col6a3 silencing is sufficient to restore contact inhibition in Taf4-/- MEFs and to suppress 3D growth by reactivating Kibra expression to induce Hippo signalling and by inducing Sfrp2 expression to antagonize Wnt signalling. All together, these results reveal a critical role for Col6a3 in regulating both Hippo and Wnt signalling to promote 3D growth, and show that the TFIID subunit TAF4 is essential to restrain the growth promoting properties of Col6a3. Our data provide new insight into the role of extra cellular matrix components in regulating cell growth. 7 samples corresponding to non-treated cells, 12 hours RA treated cells and72 hours RA treated cells were analyzed. First two conditions were done in triplicate. 72 hs point was done in duplicate.

2014-03-06 | E-GEOD-53097 | biostudies-arrayexpress

Gene expression changes associated with 3D growth of TAF4 knock out fibroblasts

2014-03-06 | GSE53098 | GEO

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