UC San Diego

Precise control of transcriptional programs that underlie metazoan development is modulated by enzymatically-active co-regulatory complexes, coupled with epigenetic strategies, but how specific histone modification enzymes are utilized to orchestrate distinct developmental programs remains unclear. Here, we report that LSD1, a histone lysine demethylase originally identified as a component of the CoREST/CtBP corepressor complex, functions in vivo as a required cofactor for both gene activation and repression programs that dictate cell type determination and differentiation during pituitary organogenesis. Remarkably, LSD1 function can be converted from activation to repression in a temporal- and cell type -specific fashion by the induced expression of two additional components of the LSD1/CoREST/CtBP complex - ZEB1, a Krüpple-like zinc finger protein and LCoR, an agonist-dependent nuclear receptor corepressor. These findings reveal critical developmental roles of a specific histone lysine demethylase and provide a potential molecular mechanism for sequential, cell type-specific gene activation and restriction events during mammalian organogenesis