Elevated polyadenylated histone gene transcription in human cancer

Abstract

Histone production is tightly restricted to S-phase to prevent genomic instability, yet human cancers with an overabundance of RNA Polymerase II (RNAPII) at histone genes are associated with aggressive cancers. To better understand histone gene overexpression in cancer, we applied a quantitative PCR assay to measure total replication-coupled histone output across the histone gene clusters using cell line models. We observed pervasive accumulation of polyadenylated histone transcripts, supported by analysis of >1,400 RNA-sequencing datasets in human cancers, with more than 70% of patients showing tumor specific increases. This alternative processing preferentially enriches for histone H2B, which lacks replication independent variants, across >8,300 tumors comprising diverse cancer types and transcriptional subtypes. We also found that disruption of nuclear components required to maintain RNAPII levels at the histone genes increased polyadenylated histone transcripts. Our results suggest that S-phase-dependent histone genes are subject to unscheduled gap phase transcription in human cancer.