Opposing LSD1 complexes function in developmental gene activation and repression programmes

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, Jean Lozach, Friederike L. Jayes, Kenneth S. Korach, Christopher K. Glass, Xiang-Dong Fu and Michael G. Rosenfeld ()
Additional contact information
Jianxun Wang: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Kathleen Scully: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Xiaoyan Zhu: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Ling Cai: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Jie Zhang: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Gratien G. Prefontaine: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Anna Krones: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Kenneth A. Ohgi: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Ping Zhu: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Ivan Garcia-Bassets: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Forrest Liu: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Havilah Taylor: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
Jean Lozach: University of California, San Diego, La Jolla, California 92093, USA
Friederike L. Jayes: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
Kenneth S. Korach: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
Christopher K. Glass: University of California, San Diego, La Jolla, California 92093, USA
Xiang-Dong Fu: University of California, San Diego, La Jolla, California 92093, USA
Michael G. Rosenfeld: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA

Nature, 2007, vol. 446, issue 7138, 882-887

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05671

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