The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors.
Nuclear all-trans retinoic acid receptors (RARs) initiate early transcriptional events which engage pluripotent cells to differentiate into specific lineages. RAR-controlled transactivation depends mostly on agonist-induced structural transitions in RAR C-terminus (AF-2), thus bridging coactivators...
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2013
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oai:doaj.org-article:65662d84c5e14954949695af67b93e712021-11-18T07:42:31ZThe elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors.1932-620310.1371/journal.pone.0064880https://doaj.org/article/65662d84c5e14954949695af67b93e712013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23762261/?tool=EBIhttps://doaj.org/toc/1932-6203Nuclear all-trans retinoic acid receptors (RARs) initiate early transcriptional events which engage pluripotent cells to differentiate into specific lineages. RAR-controlled transactivation depends mostly on agonist-induced structural transitions in RAR C-terminus (AF-2), thus bridging coactivators or corepressors to chromatin, hence controlling preinitiation complex assembly. However, the contribution of other domains of RAR to its overall transcriptional activity remains poorly defined. A proteomic characterization of nuclear proteins interacting with RAR regions distinct from the AF-2 revealed unsuspected functional properties of the RAR N-terminus. Indeed, mass spectrometry fingerprinting identified the Bromodomain-containing protein 4 (BRD4) and ALL1-fused gene from chromosome 9 (AF9/MLLT3), known to associate with and regulates the activity of Positive Transcription Elongation Factor b (P-TEFb), as novel RAR coactivators. In addition to promoter sequences, RAR binds to genomic, transcribed regions of retinoid-regulated genes, in association with RNA polymerase II and as a function of P-TEFb activity. Knockdown of either AF9 or BRD4 expression affected differentially the neural differentiation of stem cell-like P19 cells. Clusters of retinoid-regulated genes were selectively dependent on BRD4 and/or AF9 expression, which correlated with RAR association to transcribed regions. Thus RAR establishes physical and functional links with components of the elongation complex, enabling the rapid retinoid-induced induction of genes required for neuronal differentiation. Our data thereby extends the previously known RAR interactome from classical transcriptional modulators to components of the elongation machinery, and unravel a functional role of RAR in transcriptional elongation.Sébastien FlajolletChristophe RachezMaheul PlotonCéline SchulzRozenn GallaisRaphaël MétivierMichal PawlakAymeric LerayAl Amine IssulahiLaurent HéliotBart StaelsGilles SalbertPhilippe LefebvrePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e64880 (2013) |
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DOAJ |
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DOAJ |
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EN |
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Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Sébastien Flajollet Christophe Rachez Maheul Ploton Céline Schulz Rozenn Gallais Raphaël Métivier Michal Pawlak Aymeric Leray Al Amine Issulahi Laurent Héliot Bart Staels Gilles Salbert Philippe Lefebvre The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. |
| description |
Nuclear all-trans retinoic acid receptors (RARs) initiate early transcriptional events which engage pluripotent cells to differentiate into specific lineages. RAR-controlled transactivation depends mostly on agonist-induced structural transitions in RAR C-terminus (AF-2), thus bridging coactivators or corepressors to chromatin, hence controlling preinitiation complex assembly. However, the contribution of other domains of RAR to its overall transcriptional activity remains poorly defined. A proteomic characterization of nuclear proteins interacting with RAR regions distinct from the AF-2 revealed unsuspected functional properties of the RAR N-terminus. Indeed, mass spectrometry fingerprinting identified the Bromodomain-containing protein 4 (BRD4) and ALL1-fused gene from chromosome 9 (AF9/MLLT3), known to associate with and regulates the activity of Positive Transcription Elongation Factor b (P-TEFb), as novel RAR coactivators. In addition to promoter sequences, RAR binds to genomic, transcribed regions of retinoid-regulated genes, in association with RNA polymerase II and as a function of P-TEFb activity. Knockdown of either AF9 or BRD4 expression affected differentially the neural differentiation of stem cell-like P19 cells. Clusters of retinoid-regulated genes were selectively dependent on BRD4 and/or AF9 expression, which correlated with RAR association to transcribed regions. Thus RAR establishes physical and functional links with components of the elongation complex, enabling the rapid retinoid-induced induction of genes required for neuronal differentiation. Our data thereby extends the previously known RAR interactome from classical transcriptional modulators to components of the elongation machinery, and unravel a functional role of RAR in transcriptional elongation. |
| format |
article |
| author |
Sébastien Flajollet Christophe Rachez Maheul Ploton Céline Schulz Rozenn Gallais Raphaël Métivier Michal Pawlak Aymeric Leray Al Amine Issulahi Laurent Héliot Bart Staels Gilles Salbert Philippe Lefebvre |
| author_facet |
Sébastien Flajollet Christophe Rachez Maheul Ploton Céline Schulz Rozenn Gallais Raphaël Métivier Michal Pawlak Aymeric Leray Al Amine Issulahi Laurent Héliot Bart Staels Gilles Salbert Philippe Lefebvre |
| author_sort |
Sébastien Flajollet |
| title |
The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. |
| title_short |
The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. |
| title_full |
The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. |
| title_fullStr |
The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. |
| title_full_unstemmed |
The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. |
| title_sort |
elongation complex components brd4 and mllt3/af9 are transcriptional coactivators of nuclear retinoid receptors. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/65662d84c5e14954949695af67b93e71 |
| work_keys_str_mv |
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| _version_ |
1718423100395094016 |