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Nucleic Acids Research Advance Access originally published online on November 26, 2007
Nucleic Acids Research 2008 36(2):435-443; doi:10.1093/nar/gkm1058
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Nucleic Acids Research, 2008, Vol. 36, No. 2 435-443
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter

Michael Witcher1, Filippa Pettersson1, Daphne Dupéré-Richer1, Alessandra Padovani1, Leslie Summers-Deluca1, Albert S. Baldwin2 and Wilson H. Miller, Jr1,*

1Lady Davis Institute for Medical Research, Segal Cancer Centre of the SMBD Jewish General Hospital, McGill University, Montreal H3T1E2, Quebec, Canada and 2Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA

*To whom correspondence should be addressed. Tel: +514 340 8222; Fax: +(1) 514 340 8717; Email: wmiller{at}ldi.jgh.mcgill.ca

Received July 25, 2007. Revised October 18, 2007. Accepted November 9, 2007.

Transcriptional activation by nuclear hormone receptors is well characterized, but their cooperation with other signaling pathways to activate transcription remains poorly understood. Tumor necrosis factor alpha (TNF{alpha}) and all-trans retinoic acid (RA) induce monocytic differentiation of acute promyelocytic leukemia (APL) cells in a synergistic manner. We used the promoter of DIF2, a gene involved in monocytic differentiation, to model the mechanism underlying the cooperative induction of target genes by RA and TNF{alpha}. We show a functional RA response element in the DIF2 promoter, which is constitutively bound by PML/RAR{alpha} in APL cells. RA stimulates release of corepressors and recruitment of chromatin modifying proteins and additional transcription factors to the promoter, but these changes cause only a modest induction of DIF2 mRNA. Co-stimulation with RA plus TNF{alpha} facilitates binding of NF-{kappa}B to the promoter, which is crucial for full induction of transcription. Furthermore, RA plus TNF{alpha} greatly enhanced the level of RNA Pol II phosphorylation on the DIF2 promoter, via synergistic recruitment of TFIIH. We propose that RA mediates remodeling of chromatin to facilitate binding of transcription factors, which cooperate to enhance Pol II phosphorylation, providing a mechanism whereby nuclear receptors interact with other signaling pathways on the level of transcription.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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