H2A.B is a tissue-specific histone variant, which is involved in the activation of gene expression and promotion of mRNA splicing in the testis and the brain. Epigenetic regulators in the testis are commonly observed to be ectopically expressed in cancer, often playing a pivotal role in carcinogenesis. Previously, our lab identified that H2A.B is systematically overexpressed in one type of cancer, Hodgkin Lymphoma (HL). The main aim of my project is to understand the role of H2A.B-mediated epigenetic regulation of the oncogenesis of HL. One of the main epigenetic mechanisms that control chromatin make-up is the deposition of histone variants and alteration of histone by post-translational modification (PTM). As such, we discovered that H2A.B incorporates into the chromatin of cancer-driving Hodgkin Reed-Sternberg cells in HL and identified, for the first time, PTMs of H2A.B that play a critical role in its incorporation into chromatin and function. We also identified epigenetic “readers” of H2A.B PTMs using proteomic approaches. In addition, a novel splicing isoform of protein arginine methyltransferase was identified as the epigenetic “writer”. Our finding uncovered a novel H2A.B-mediated epigenetic mechanism that H2A.B exerts in the cancer context and revealed new aspects of the histone code hypothesis.