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Opposing LSD1 complexes function in developmental gene activation and repression programmes

Nature volume 446, pages 882–887 (2007)Cite this article

Abstract

Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1—a component of the CoREST-CtBP co-repressor complex—is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co-activator or co-repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Krüppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co-repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs.

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Figure 1: LSD1 is required for cell-type-specific pituitary hormone expression.
Figure 2: LSD1 is involved in regulatory programmes in pituitary development.
Figure 3: LSD1 regulates gene expression during pituitary development.
Figure 4: Postpartum induction of the LSD1 complex in Gh restriction events.
Figure 5: The LSD1 complex has roles in restriction of Gh expression in lactotropes.

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Acknowledgements

We thank C. Nelson and L.Wang for technical assistance, L. Olson for generating Pitx1 Cre+ mice, Y. Geng for the Ccne1 promoter reporter, W. Herr for the generous gift of anti-WDR5 antibody, A. Gonzalez, J. Liu for advice on reagents, and J. Hightower and M. Fisher for figure and manuscript preparation. M.G.R is an investigator with HHMI. This work was supported by grants from the NIH and NCI to M.G.R., C.K.G. and X.-D.F.

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Author notes

  1. Kathleen Scully, Xiaoyan Zhu and Ling Cai: These authors contributed equally to this work.

Authors and Affiliations

  1. Department and School of Medicine, Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA,

    Jianxun Wang, Kathleen Scully, Xiaoyan Zhu, Ling Cai, Jie Zhang, Gratien G. Prefontaine, Anna Krones, Kenneth A. Ohgi, Ping Zhu, Ivan Garcia-Bassets, Forrest Liu, Havilah Taylor & Michael G. Rosenfeld

  2. Molecular Pathology Graduate Program,,

    Jianxun Wang

  3. Department of Biology Graduate Program,,

    Ling Cai

  4. Department of Cellular and Molecular Medicine, Department and School of Medicine, University of California, San Diego, La Jolla, California 92093, USA,

    Jean Lozach, Christopher K. Glass & Xiang-Dong Fu

  5. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA,

    Friederike L. Jayes & Kenneth S. Korach

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Wang, J., Scully, K., Zhu, X. et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 446, 882–887 (2007). https://doi.org/10.1038/nature05671

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