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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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.).
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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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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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DOI: https://doi.org/10.1038/nn.3490
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