Fig. 6

Schematic representation of the epigenetic mechanisms triggering Nr5a1 expression during the early steps of gonadotrope specification. In progenitors, the chromatin of the Nr5a1 locus is mainly in a repressed conformation: It is not yet accessible to TFs, DNA is methylated, and the gene is not expressed. While the promoter does not yet bear any epigenetic marks of activation, the α enhancer is already primed. Interestingly, the α enhancer is already looping on the pituitary 1G promoter and a limited chromatin accessibility of the α enhancer allows some binding of ligand-activated ERα. ERα recruits only a limited amount of P300 on the enhancer, allowing a low level of histone acetylation. The α enhancer is thus in a bivalent state and the gene is on the verge of activation. In immature gonadotropes, CpGs are demethylated and chromatin accessibility on the α enhancer increased dramatically, as well as P300 recruitment and histone acetylation. These epigenetic modifications are ERα dependent. Activation of the α enhancer allows histone acetylation and recruitment of RNA Pol II on the pituitary 1G promoter and hence Nr5a1 transcription. The transition between α enhancer-repressed and activated states is probably due in part to recruitment of ERα co-activators that would be repressed or not yet expressed in progenitors