The proliferation and differentiation of muscle precursor cells require myogenic 
regulatory factors and chromatin modifiers whose concerted action dynamically 
regulates access to DNA and allows reprogramming of cells towards terminal 
differentiation. Type 2 deiodinase (D2), the thyroid hormone (TH)-activating 
enzyme, is sharply upregulated during myoblast differentiation, whereas type 3 
deiodinase (D3), the TH-inactivating enzyme, is downregulated. The molecular 
determinants controlling synchronized D2 and D3 expression in muscle 
differentiation are completely unknown. Here, we report that the histone H3 
demethylating enzyme (LSD-1) is essential for transcriptional induction of D2 
and repression of D3. LSD-1 relieves the repressive marks (H3-K9me2-3) on the 
Dio2 promoter and the activation marks (H3-K4me2-3) on the Dio3 promoter. LSD-1 
silencing impairs the D2 surge in skeletal muscle differentiation while inducing 
D3 expression thereby leading to a global decrease in intracellular TH 
production. Furthermore, endogenous LSD-1 interacts with FoxO3a, and abrogation 
of FoxO3-DNA binding compromises the ability of LSD-1 to induce D2. Our data 
reveal a novel epigenetic control of reciprocal deiodinases expression and 
provide a molecular mechanism by which LSD-1, through the opposite regulation of 
D2 and D3 expression, acts as a molecular switch that dynamically finely tunes 
the cellular needs of active TH during myogenesis.