Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse 
developmental contexts, including hematopoiesis and oncogenesis. Transcriptional 
repression by Gfi proteins requires the conserved SNAG domain. To elucidate the 
function of Gfi proteins, we purified Gfi-1b complexes and identified 
interacting proteins. Prominent among these is the corepressor CoREST, the 
histone demethylase LSD1, and HDACs 1 and 2. CoREST and LSD1 associate with 
Gfi-1/1b via the SNAG repression domain. Gfi-1b further recruits these cofactors 
to the majority of target gene promoters in vivo. Inhibition of CoREST and LSD1 
perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as 
well as primary erythroid progenitors. LSD1 depletion derepresses Gfi targets in 
lineage-specific patterns, accompanied by enhanced histone 3 lysine 4 
methylation at the respective promoters. Overall, we show that chromatin 
regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi 
proteins. Lineage-restricted deployment of these cofactors through interaction 
with Gfi proteins controls hematopoietic differentiation.