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Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals

Nature Neuroscience volume 16, pages 1191–1198 (2013)Cite this article

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Abstract

Hox genes controlling motor neuron subtype identity are expressed in rostrocaudal patterns that are spatially and temporally collinear with their chromosomal organization. Here we demonstrate that Hox chromatin is subdivided into discrete domains that are controlled by rostrocaudal patterning signals that trigger rapid, domain-wide clearance of repressive histone H3 Lys27 trimethylation (H3K27me3) polycomb modifications. Treatment of differentiating mouse neural progenitors with retinoic acid leads to activation and binding of retinoic acid receptors (RARs) to the Hox1–Hox5 chromatin domains, which is followed by a rapid domain-wide removal of H3K27me3 and acquisition of cervical spinal identity. Wnt and fibroblast growth factor (FGF) signals induce expression of the Cdx2 transcription factor that binds and clears H3K27me3 from the Hox1–Hox9 chromatin domains, leading to specification of brachial or thoracic spinal identity. We propose that rapid clearance of repressive modifications in response to transient patterning signals encodes global rostrocaudal neural identity and that maintenance of these chromatin domains ensures the transmission of positional identity to postmitotic motor neurons later in development.

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Figure 1: Domain-wide clearance of repressive histone modifications and changes in Hox gene expression in response to retinoic acid.
Figure 2: Patterns of Hox gene expression in Suz12β-gal/β-gal cells differentiated into motor neurons.
Figure 3: Wnt3A and FGF2 induce Cdx2 and caudalize differentiating motor neurons.
Figure 4: Cdx2 induces caudal Hox gene expression during motor neuron differentiation.
Figure 5: Cdx2 controls Hox gene expression and chromatin modifications directly.
Figure 6: The sequential activity of RAR and Cdx2 establishes two distinct chromatin states.

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Acknowledgements

We thank V. Korinek (Institute of Molecular Genetics, Prague) for purified Wnt3A protein, G. Daley (Harvard Medical School) for the Cdx2 construct, M. Kyba (University of Minnesota) for sharing reagents for construction of the inducible Cdx2 ESC line and T. Jessell (Columbia University) and J. Dasen (New York University) for sharing antibodies and for constructive discussion of our findings. E.O.M. was the David and Sylvia Lieb Fellow of the Damon Runyon Cancer Research Foundation (DRG-1937-07), and this work was supported by The Leona M. and Harry B. Helmsley Charitable Trust, US National Institutes of Health grants P01 NS055923 (D.K.G. and H.W.) and R01 NS058502 and NS078097 (H.W.) and The Richard and Susan Smith Family Foundation, Chestnut Hill, Massachusetts (L.A.B.).

Author information

Author notes

  1. Mirza Peljto

    Present address: Present address: Flagship Biosciences, Boulder, Colorado, USA.,

  2. Esteban O Mazzoni, Shaun Mahony and Mirza Peljto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Medical Center, New York, New York, USA

    Esteban O Mazzoni, Mirza Peljto, Tulsi Patel & Hynek Wichterle

  2. Department of Neurology, Columbia University Medical Center, New York, New York, USA

    Esteban O Mazzoni, Mirza Peljto, Tulsi Patel & Hynek Wichterle

  3. Department of Neuroscience, Columbia University Medical Center, New York, New York, USA

    Esteban O Mazzoni, Mirza Peljto, Tulsi Patel & Hynek Wichterle

  4. Department of Biology, New York University, New York, New York, USA

    Esteban O Mazzoni

  5. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Shaun Mahony, Christopher Reeder & David K Gifford

  6. Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, Pennsylvania, USA

    Shaun Mahony

  7. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Seraphim R Thornton & Laurie A Boyer

  8. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA

    Scott McCuine & Richard A Young

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Contributions

E.O.M., S. Mahony, D.K.G. and H.W. conceived the experiments, analyzed the data and wrote the manuscript. E.O.M. generated and validated inducible cell lines and performed cell differentiations and expression analyses. S. Mahony and C.R. performed all computational and statistical analyses of genomic, expression and sequencing data. M.P. and T.P. performed and optimized caudalization experiments. S.R.T. and L.A.B. performed analysis of Prc2-null and hypomorph cell lines. S. McCuine and R.A.Y. performed ChIP-chip experiments.

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Correspondence to Esteban O Mazzoni, David K Gifford or Hynek Wichterle.

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The authors declare no competing financial interests.

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Mazzoni, E., Mahony, S., Peljto, M. et al. Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals. Nat Neurosci 16, 1191–1198 (2013). https://doi.org/10.1038/nn.3490

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