Gene activation of HOX clusters is an early event in embryonic development. These genes are highly expressed and been active in the vertebrate nervous system. Based on the presence of retinoic Acid Response Element (RARE) in regulatory region of many of HOX genes, it is deduced that retinoic acid can influence on epigenetic and consequently expression pattern of HOX during RA-induced differentiation of embryonic model systems. In this investigation, expression level as well as epigenetic regulation of several HOX genes of the four A-D clusters was analyzed in human embryonic stem cells (hESC), and also through their neural induction, in the presence and absence of retinoic acid. 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. Keywords: HOX, retinoic acid, H3K27-demethylase, UTX, JMJD.