Transcription profiling of pituitary glands from wild type and LSD1 knock-out mice

Precise control of transcriptional programs underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies, but how specific members of histone modification enzyme families such as histone methyltransferases and demethylases are utilized in vivo to simultaneously orchestrate distinct developmental gene activation and repression programs remains unclear. Here, we report that the initially-described histone lysine demethylase, LSD1, a component of the CoREST/CtBP corepressor complex, is required for late cell-lineage determination and differentiation during pituitary organogenesis. Surprisingly, LSD1 acts primarily on target gene activation programs, as well as in gene repression programs, based on recruitment of distinct LSD1-containing coactivator or corepressor complexes. Intriguingly, LSD1-dependent gene repression programs can be extended late in development with the induced expression of ZEB1, a Kr.pple-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CtBP/CoREST corepressor complex, causing repression of an additional cohort of genes, such as GH, that previously required LSD1 for activation.