Skip to main content
  • Poster presentation
  • Open access
  • Published:

The 4-D landscape of the inflammatory response

Background

It is widely accepted that chromatin ‘responds’ to physiological cues via protein:DNA interactions and nucleosome rearrangement [1, 2], and that transcription plays a key role in its higher-order organization [3]. What remains elusive is how the nuclear landscape reshapes, in 3-D space and time, to facilitate such responses to unfold.

Materials and methods

We add tumour necrosis factor α (TNFα) to primary human endothelial cells and induce the inflammatory cascade; this is orchestrated by the transcription factor NF-κB [4]. We monitor the response for 0-85 min post-induction using ChIP nucleosome-positioning studies, and chromosome conformation capture, all coupled to next-generation sequencing. We also apply a new approach, where the isolation of ‘transcription factories’ [5] is followed by RNA-seq to uncover nascent transcriptomes.

Results

First, we redefine early, intermediate, late, and oscillating TNFα-responsive genes, based on changing levels of nascent RNA. We then examine how these co-associate in specialized ‘factories’, some of which further specialize in transcribing responsive non-coding genes [6]. Contacts are driven by NF-κB, and evolve as genes are differentially turned on and off over time. We also monitor nucleosome rearrangements genome-wide; these correlate with poised promoters before induction, and with nucleosome depletion as a result of transcriptional activation, NF-κB binding, enhancer activity in TNFα-stimulated chromosomal domains.

Conclusions

We provide evidence for a prompt, within <30 min, reshaping of the genome in response to inflammation. This entails de novo associations of co-regulated coding and non-coding sequences in specialized 3-D networks that evolve over time, as well as extensive nucleosome depletion. We expect all extracellular cues to signal through analogous specialized networks and reassess our parsimonious model [7] for transcriptional regulation accordingly.

References

  1. Grøntved L, Hager GL: Impact of chromatin structure on PR signaling: transition from local to global analysis. Mol Cell Endocrinol. 2012, 357: 30-36. 10.1016/j.mce.2011.09.006.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Turner BM: The adjustable nucleosome: an epigenetic signaling module. Trends Genet. 2012, 28: 436-444. 10.1016/j.tig.2012.04.003.

    Article  CAS  PubMed  Google Scholar 

  3. Papantonis A, Cook PR: Genome architecture and the role of transcription. Curr Opin Cell Biol. 2010, 22: 271-276. 10.1016/j.ceb.2010.03.004.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Smale ST: Hierarchies of NF-KB target-gene regulation. Nat Immunol. 2011, 12: 689-694.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Melnik S, Deng B, Papantonis A, Baboo S, Carr IM, Cook PR: The proteomes of transcription factories containing RNA polymerases I, II or III. Nat Methods. 2011, 8: 963-968. 10.1038/nmeth.1705.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Papantonis A, Kohro T, Baboo S, Larkin JD, Deng B, Short P, Tsutsumi S, Taylor S, Kanki Y, Kobayashi M, Li G, Poh HM, Ruan X, Aburatani H, Ruan Y, Kodama T, Wada Y, Cook PR: TNFα signals through specialized factories where responsive coding and miRNA genes are transcribed. EMBO J. 2012, 31: 4404-4414. 10.1038/emboj.2012.288.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Kolovos P, Knoch TA, Grosveld FG, Cook PR, Papantonis A: Enhancers and silencers: an integrated and simple model for their function. Epigenetics & Chromatin. 2012, 5: 1-10.1186/1756-8935-5-1.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by the BBSRC via the ERASysBio+/FP7 initiative.

Author information

Authors and Affiliations

Authors

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Papantonis, A. The 4-D landscape of the inflammatory response. Epigenetics & Chromatin 6 (Suppl 1), P64 (2013). https://doi.org/10.1186/1756-8935-6-S1-P64

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/1756-8935-6-S1-P64

Keywords