Gene activation of HOX clusters is an early event in embryonic development. These genes are highly expressed and active in the vertebrate nervous system. Based on the presence of retinoic acid response elements (RAREs) in the regulatory region of many of the HOX genes, it is deduced that retinoic acid (RA) can influence epigenetic regulation and consequently the expression pattern of HOX during RA-induced differentiation of embryonic model systems. In this investigation, the expression level as well as the epigenetic regulation of several HOX genes of the 4 A-D clusters was analyzed in human embryonic stem cells, and also through their neural induction, in the presence and absence of RA. Expression analysis data significantly showed increased mRNA levels of all examined HOX genes in the presence of RA. Epigenetic analysis of the HOX gene regulatory regions also showed a significant decrease in methylation of histone H3K27 parallel to an absolute preferential incorporation of the demethylase UTX rather than JMJD3 in RA-induced neural differentiated cells. This finding clearly showed the functional role of UTX in epigenetic alteration of HOX clusters during RA-induced neural differentiation; the activity could not be detectable for the demethylase JMJD3 during this developmental process.