1. Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
2. Molecular Pathology Graduate Program,
3. Department of Biology Graduate Program,
4. Department of Cellular and Molecular Medicine, Department and School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
5. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
6. These authors contributed equally to this work.

Correspondence to: Michael G. Rosenfeld¹ Correspondence and requests for materials should be addressed to M.G.R. (Email: mrosenfeld@ucsd.edu).

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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