Epigenetic control of type 2 and 3 deiodinases in myogenesis: Role of Lysine-specific Demethylase enzyme and FoxO3

Raffaele Ambrosio, Valentina Damiano, Annarita Sibilio, Maria Angela De Stefano, Vittorio Enrico Avvedimento, Domenico Salvatore, Monica Dentice

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3551-3562
Number of pages12
JournalNucleic Acids Research
Issue number6
Publication statusPublished - Apr 2013

ASJC Scopus subject areas

  • Genetics


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