Precise regulation of Major Histocompatibility class II (MHC II) genes plays important roles in initiation, propagation and termination of adaptive immune responses by controlling antigen presentation to CD4+ T cells. MHC II genes are constitutively expressed in only a few cell types and are inducibly expressed by the inflammatory response cytokine interferon gamma (IFNγ) in all nucleated cells. The regulation of MHC II is tightly controlled by a Master Regulator, the class II transactivator (CIITA), which is a general regulator of both constitutive and inducible MHC II expression. Although much is known about the transcription factors necessary for CIITA expression, less is known about the epigenetic modifications and the requisite enzymes needed to provide these transcription factors access to DNA. We show here that multiple epigenetic changes occur at the IFNγ inducible CIITA promoter within 20' of IFNγ stimulation and that these changes correlate with the opening of the promoter and the initiation of transcription. Our study links these rapidly occurring epigenetic events at the inducible CIITA promoter to decreased promoter binding of the histone methyltransferase EZH2, and shows that decreased promoter binding of EZH2 transforms this previously tightly regulated and cytokine inducible promoter into a constitutively active and dysregulated gene.