The Polycomb/Trithorax Responsive Elements (PRE/TREs) are the cis-regulatory sequences that interact with both repressive (PcG) as well as activating (TrxG) complexes. However, most of the mammalian PREs are demonstrated to interact with the repressive polycomb (PcG) complexes only. We have carried out an unbiased search for proteins interacting with human PRE-PIK3C2B (hPRE-PIK3C2B) based on DNA affinity purification followed by mass spectrometry and identified MLL, MLL4 and WDR87 among other proteins in three biological replicates in HEK, U87 and HeLa cell lines. The hPRE-PIK3C2B interacts with the members of multiple activating complexes (COMPASS-like). The increase in the interaction of MLL and MLL4 on depletion of YY1 and the increase in the enrichment of YY1 and EZH2 upon MLL knockdown at the hPRE-PIK3C2B indicate the dual occupancy and suggest a concentration dependent enrichment of the activator or the repressor complex at hPRE-PIK3C2B. Further, we show that the hPRE-PIK3C2B interacts with the Drosophila homologues of PcG and TrxG proteins in transgenic flies. Here, we found that there is an increased enrichment of Pc (Polycomb) in comparison to Trx (TrxG protein) at hPRE-PIK3C2B in the Drosophila transgenic flies and this seems to be the default state while the balance is tipped towards the trithorax complex in PcG mutants. To the best of our knowledge, this is one of the early demonstrations of human PRE acting as a TRE without any sequence alteration.