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A histone H3 lysine 27 demethylase regulates animal posterior development

Author

Listed:
  • Fei Lan

    (Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA)

  • Peter E. Bayliss

    (Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • John L. Rinn

    (Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, California 94305, USA)

  • Johnathan R. Whetstine

    (Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA)

  • Jordon K. Wang

    (Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, California 94305, USA)

  • Shuzhen Chen

    (Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA)

  • Shigeki Iwase

    (Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA)

  • Roman Alpatov

    (Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA)

  • Irina Issaeva

    (Weizmann Institute of Science)

  • Eli Canaani

    (Weizmann Institute of Science)

  • Thomas M. Roberts

    (Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA)

  • Howard Y. Chang

    (Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, California 94305, USA)

  • Yang Shi

    (Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA)

Abstract

The recent discovery of a large number of histone demethylases suggests a central role for these enzymes in regulating histone methylation dynamics. Histone H3K27 trimethylation (H3K27me3) has been linked to polycomb-group-protein-mediated suppression of Hox genes and animal body patterning, X-chromosome inactivation and possibly maintenance of embryonic stem cell (ESC) identity. An imbalance of H3K27 methylation owing to overexpression of the methylase EZH2 has been implicated in metastatic prostate and aggressive breast cancers. Here we show that the JmjC-domain-containing related proteins UTX and JMJD3 catalyse demethylation of H3K27me3/2. UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts, in which HOX genes are differentially expressed, but is selectively excluded from the HOX loci in ESCs, in which HOX genes are largely silent. Consistently, RNA interference inhibition of UTX led to increased H3K27me3 levels at some HOX gene promoters. Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homologue resulted in mis-regulation of hox genes and a striking posterior developmental defect, which was partially rescued by wild-type, but not by catalytically inactive, human UTX. Taken together, these findings identify a small family of H3K27 demethylases with important, evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior–posterior development.

Suggested Citation

  • Fei Lan & Peter E. Bayliss & John L. Rinn & Johnathan R. Whetstine & Jordon K. Wang & Shuzhen Chen & Shigeki Iwase & Roman Alpatov & Irina Issaeva & Eli Canaani & Thomas M. Roberts & Howard Y. Chang &, 2007. "A histone H3 lysine 27 demethylase regulates animal posterior development," Nature, Nature, vol. 449(7163), pages 689-694, October.
  • Handle: RePEc:nat:nature:v:449:y:2007:i:7163:d:10.1038_nature06192
    DOI: 10.1038/nature06192
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    Cited by:

    1. Wenxian Wang & Hyeyoung Cho & Jae W. Lee & Soo-Kyung Lee, 2022. "The histone demethylase Kdm6b regulates subtype diversification of mouse spinal motor neurons during development," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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