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A central role for TFIID in the pluripotent transcription circuitry

Nature volume 495, pages 516–519 (2013)Cite this article

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Abstract

Embryonic stem (ES) cells are pluripotent and characterized by open chromatin and high transcription levels, achieved through auto-regulatory and feed-forward transcription factor loops1,2. ES-cell identity is maintained by a core of factors including Oct4 (also known as Pou5f1), Sox2, Klf4, c-Myc (OSKM) and Nanog2,3,4, and forced expression of the OSKM factors can reprogram somatic cells into induced pluripotent stem cells (iPSCs) resembling ES cells5,6. These gene-specific factors for RNA-polymerase-II-mediated transcription recruit transcriptional cofactors and chromatin regulators that control access to and activity of the basal transcription machinery on gene promoters7,8. How the basal transcription machinery is involved in setting and maintaining the pluripotent state is unclear. Here we show that knockdown of the transcription factor IID (TFIID) complex affects the pluripotent circuitry in mouse ES cells and inhibits reprogramming of fibroblasts. TFIID subunits and the OSKM factors form a feed-forward loop to induce and maintain a stable transcription state. Notably, transient expression of TFIID subunits greatly enhanced reprogramming. These results show that TFIID is critical for transcription-factor-mediated reprogramming. We anticipate that, by creating plasticity in gene expression programs, transcription complexes such as TFIID assist reprogramming into different cellular states.

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Figure 1: High expression of TFIID is required for maintaining ES cell identity.
Figure 2: TFIID is part of the pluripotency circuitry and is required for reprogramming.
Figure 3: TFIID potentiates reprogramming to pluripotent cells.
Figure 4: TAF contributions to reprogramming and developmental potential of iPSCs.

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ArrayExpress

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DNA microarray data have been deposited in the public ArrayExpress database under accessions E-TABM-1217 and E-TABM-1218.

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Acknowledgements

This work is funded by the Netherlands Proteomics Centre, Netherlands Organization for Scientific Research (TOP#700.57.302), Deutsche Forschungsgemeinschaft (DFG Priority Program SPP 1356/2) and the European Union (EUTRACC LSHG-CT-2006-037445). We thank M. Groot Koerkamp and D. van Leenen for microarray analysis, M. de Bruijn and O. Kranenburg for advice on lentiviral knockdown experiments, F. Stewart for help with BAC recombineering, I. Davidson and R. Tjian for TAF cDNA constructs, N. Outchkourov for the GFP-tagging vector, B. Roeder, T. Oelgeschläger and G. Kops for antibodies, M. Stehling for help with the FACS analyses, A. Schambach and C. Baum for the lentiviral OSKM vector, M. Sgodda and T. Cantz for human fibroblasts, M. Radstaak for assistance with human iPSC culture and P. de Graaf, N. Jelluma and M. Vermeulen for critical reading of the manuscript.

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Author notes

  1. W. W. M. Pim Pijnappel, Atze J. Bergsma, Erik van der Wal & Dong Wook Han

    Present address: Present addresses: Department of Pediatrics and Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands (W.W.M.P.P.; A.J.B.; E.v.d.W.); Department of Stem Cell Biology, School of Medicine, SMART Institute of Advanced Biomedical Science, Konkuk University, 143701 Seoul, Republic of Korea (D.W.H.).,

  2. W. W. M. Pim Pijnappel and Daniel Esch: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands ,

    W. W. M. Pim Pijnappel, Marijke P. A. Baltissen, Atze J. Bergsma, Phillip Lijnzaad, Katrin Sameith, Frank C. P. Holstege & H. T. Marc Timmers

  2. Netherlands Proteomics Center, 3584 CH Utrecht, The Netherlands ,

    W. W. M. Pim Pijnappel, Marijke P. A. Baltissen, Nikolai Mischerikow, A. F. Maarten Altelaar, Albert J. R. Heck & H. T. Marc Timmers

  3. Department of Pediatrics and Department of Clinical Genetics, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands,

    W. W. M. Pim Pijnappel & Erik van der Wal

  4. Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany ,

    Daniel Esch, Guangming Wu, Erik van der Wal, Dong Wook Han, Hermann vom Bruch, Sören Moritz, Holm Zaehres & Hans R. Schöler

  5. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, The Netherlands ,

    Nikolai Mischerikow, A. F. Maarten Altelaar & Albert J. R. Heck

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Contributions

W.W.M.P.P. and H.T.M.T. initiated the project. W.W.M.P.P., D.E., H.Z., A.J.R.H., F.C.P.H., H.R.S. and H.T.M.T. designed the experiments. M.P.A.B. and W.W.M.P.P. performed lentiviral knockdown and mRNA analysis. N.M., A.F.M.A., W.W.M.P.P. and A.J.R.H. performed and analysed the mass spectrometry experiments. W.W.M.P.P. and F.C.P.H. performed and supervised the mRNA profiling experiments. A.J.B. and W.W.M.P.P. performed the ChIP and enhancer analysis. W.W.M.P.P., D.E., E.v.d.W., D.W.H., H.v.B., S.M., H.Z. and H.T.M.T. performed the reprogramming experiments. P.L. and K.S. contributed to the statistical analysis. G.W. performed the animal experiments. W.W.M.P.P. and H.T.M.T. wrote the manuscript. All authors approved the manuscript.

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Correspondence to H. T. Marc Timmers.

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The authors declare no competing financial interests.

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Pijnappel, W., Esch, D., Baltissen, M. et al. A central role for TFIID in the pluripotent transcription circuitry. Nature 495, 516–519 (2013). https://doi.org/10.1038/nature11970

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