It has been well established that epigenetic mechanisms play an essential role in cell differentiation and maintenance of cell function. Not surprisingly, corruption of epigenetic machinery results in disastrous consequences including oncogenesis. For more than 20 years, it has been known that various somatic cancers display an aberrant activation of germ cell specific genes (known as cancer testis [C/T] antigens), and many of these proteins are in fact regulators of the epigenome. Recently, we discovered that a testis-specific histone H2A variant, H2A.B, is abnormally upregulated in Hodgkin lymphoma (HL) primary tumours. HL accounts for 5.6% of haematological cancers, yet very little is known about the mechanisms that drive HL carcinogenesis. This raised a possibility that H2A.B has been hijacked by HL to promote oncogenesis and survival.
We found that, like its mouse homologue in spermatogenesis, H2A.B1,2,3, is enriched at the TSS and the exon-intron boundaries of active genes but unexpectedly it has a novel, HL-specific enrichment, on promoters and gene bodies of ribosomal protein genes. We also uncovered a novel HL-cancer specific behaviour of H2A.B, localisation to nucleoli, where H2A.B-nucleosomes are enriched on the ribosomal DNA tandem repeats that code for rRNA and directly interact with RNA polymerase I. Furthermore, we mapped for the first time the post-translational modification of H2A.B and showed that they have different functional burden. The H2A.B knock-down results in marked decrease in HL cell proliferation. Taken together, our findings imply that H2A.B is not only a new marker for HL but is a novel functional epigenetic regulator of HL that has oncogenic properties.