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Chromatin accessibility

Pioneers conquer core histones at the chromatin frontier

Nature Structural & Molecular Biology volume 30, pages 1050–1053 (2023)Cite this article

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Pioneer transcription factors access gene regulatory sites embedded within chromatin. They drive gene expression programs vital for cell fate decisions and cellular reprogramming, but how they engage nucleosomal sites at the molecular level is unclear. New results show that they engage histones and collaborate to overcome the nucleosome barrier.

Pioneer transcription factors (PFs) are sequence-specific transcription factors (TFs) that bind chromatin-embedded gene regulatory regions. Their binding promotes the engagement of other TFs and chromatin remodeling enzymes that promote chromatin opening, which activates gene networks that orchestrate cellular reprogramming1,2. We have good insights into how TFs engage their cognate exposed DNA elements, but what enables PFs to access and bind their binding sites within chromatinized promoters and enhancers is not well established. The physiological target sequence of PFs is packed into nucleosomes in vivo, so PFs may compete with histones to access nucleosomal DNA. Direct interactions between a PF and core histones could play a key role in accessing chromatin3, but experimental evidence for this has been scarce2. Three studies now provide structural, functional and mechanistic insights into how PFs recognize nucleosomal DNA and core histones, how histone modifications affect PF function and how they establish nucleosome positioning to enable the opening of chromatin through cooperative TF interactions4,5,6. The first two studies by Michael et al.6 in Nature and Donovan et al.5 in Molecular Cell focused on the large family of basic helix–loop–helix (bHLH) TFs, which share similar DNA binding domains, bind genomic elements called E-boxes and regulate circadian rhythm, glucose responses, differentiation and cell proliferation. Interestingly, some bHLH proteins can act as PFs, while others cannot, so the studies explored how these PFs and TFs engage nucleosomes and cooperate with each other. The third study by Sinha et al.4 in Nature addressed how histone modifications affect PF function on a nucleosome assembled on a native DNA sequence.

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Fig. 1: Histone and histone–tail interactions of pioneer factors.
Fig. 2: Models of chromatin opening by PFs.

References

  1. Zaret, K. S. Annu. Rev. Genet. 54, 367–385 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cirillo, L. A. et al. Mol. Cell 9, 279–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Michael, A. K. & Thoma, N. H. Cell 184, 3599–3611 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Sinha, K. K., Bilokapic, S., Du, Y., Malik, D. & Halic, M. Nature 619, 378–384 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Donovan, B. T. et al. Mol. Cell 83, 1251–1263 (2023).

    Article  CAS  PubMed  Google Scholar 

  6. Michael, A. K. et al. Nature 619, 385–393 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Michael, A. K. et al. Science 368, 1460–1465 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Soufi, A. et al. Cell 161, 555–568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yan, C., Chen, H. & Bai, L. Mol. Cell 71, 294–305 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Donovan, B. T., Chen, H., Jipa, C., Bai, L. & Poirier, M. G. eLife 8, e43008 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cirillo, L. A. & Zaret, K. S. Mol. Cell 4, 961–969 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Shogren-Knaak, M. et al. Science 311, 844–847 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, Q., Yang, R., Korolev, N., Liu, C. F. & Nordenskiold, L. J. Mol. Biol. 429, 2075–2092 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J. & Cramer, P. Nature 580, 669–672 (2020).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funding was provided by the DFG (Project-IDs 453441129, 213249687 - SFB 1064 and 325871075 - SFB 1309) and LMU Munich.

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Authors and Affiliations

  1. Biomedical Center Munich, Faculty of Medicine, LMU Munich, Planegg, Germany

    Magdalena Murawska, Andreas G. Ladurner & Carla E. Margulies

  2. International Max Planck Research School (IMPRS) for Molecular Life Sciences, Planegg, Germany

    Andreas G. Ladurner

  3. Eisbach Bio GmbH, Planegg, Germany

    Andreas G. Ladurner

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  1. Magdalena Murawska
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  2. Andreas G. Ladurner
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  3. Carla E. Margulies
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Correspondence to Magdalena Murawska or Carla E. Margulies.

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Competing interests

A.G.L. is a founder, CSO and managing director of Eisbach Bio GmbH, a biotechnology company in oncology and virology. All other authors declare no competing interests.

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Murawska, M., Ladurner, A.G. & Margulies, C.E. Pioneers conquer core histones at the chromatin frontier. Nat Struct Mol Biol 30, 1050–1053 (2023). https://doi.org/10.1038/s41594-023-01058-9

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