As with other sensory mechanisms, determination of the thermal-control set point is refined during a critical period of development by alterations in cellular properties in the frontal hypothalamus. These alterations in hypothalamic plasticity are achieved by renewal of the protein repertoire via activation or silencing of gene transcription, both of which are regulated by histone modifications. This study demonstrates induction of global histone H3 lysine 27 (H3K27) dimethylation, with no changes in its trimethylation levels, in the frontal hypothalamus, as well as at the promoter of the brain-derived neurotrophic factor (BDNF) gene during thermal-control establishment. Furthermore, antisense ‘knockdown’ of the H3K27-specific methyltransferase, enhancer of zeste 2, which was induced in correlation with the dimethylation of H3K27, inhibited Bdnf mRNA expression and disrupted the establishment of thermoregulation. This phenotypic effect was partially rescued by intracranial injection of BDNF. The presented findings highlight the specific epigenetic role of chromatin modifications in thermal-control establishment.