Chromatin regulators control cellular differentiation by orchestrating dynamic 
developmental gene expression programs, and hence, malfunctions in the 
regulation of chromatin state contribute to both developmental disorders and 
disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins 
ASsociated with Set1) protein family that implements histone H3 lysine 4 
monomethylation (H3K4me1) at enhancers, is essential for embryonic development 
and functions as a pancancer tumor suppressor. We define the roles of 
Mll4/COMPASS and its catalytic activity in the maintenance and exit of 
ground-state pluripotency in murine embryonic stem cells (ESCs). Mll4 is 
required for ESC to exit the naive pluripotent state; however, its intrinsic 
catalytic activity is dispensable for this process. The depletion of the H3K4 
demethylase Lsd1 (Kdm1a) restores the ability of Mll4 null ESCs to transition 
from naive to primed pluripotency. Thus, we define an opposing regulatory axis, 
wherein Lsd1 and associated co-repressors directly repress Mll4-activated gene 
targets. This finding has broad reaching implications for human developmental 
syndromes and the treatment of tumors carrying Mll4 mutations.