BioProject

Histone demethylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity, by still poorly understood mechanisms. More...

Histone demethylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity, by still poorly understood mechanisms. Here we examined the role played by the histone demethylase Kdm3a, which demethylates lysine 9 of histone H3, during cellular differentiation. Using F9 mouse embryonal carcinoma cells as a model for progression through terminal differentiation, we showed that Kdm3a is essential to differentiation into parietal endoderm-like (PE) cells. On gene expression microarrays, we found several genes whose expression is upregulated by Kdm3a during endoderm differentiation, including the three developmental master players Dab2, Pdlim4, and FoxQ1. The role of Kdm3a as a transcriptional activator of these genes was correlated with its effect by demethylating dimethyl-lysine 9 of histone H3 (H3K9me2) at their promoters. We further demonstrated that Dab2 depletion, like Kdm3a depletion, prevents F9 cells from fully differentiating into PE cells. Nevertheless, the only overexpression of Dab2 in Kdm3a-depleted cells is not sufficient to completely restore the PE differentiation in Kdm3a-knockdown cells. Overall, our findings reveal that Kdm3a is crucial for progression through terminal differentiation, likely by regulating the expression of a set of master players in endoderm differentiation. The emergence of Kdm3a as a key modulator of cell fate decision strengthens the notion that histone demethylases are at the nexus of cell differentiation and development. Overall design: Total RNA obtained from control and Kdm3a-depleted F9 cells at different differentiation stages Less...