Distinct roles of histone H2B ubiquitination at promoters and coding regions of Pol II-transcribed stress genes.

BACKGROUND: The histone code, comprised of diverse histone post-translational modifications, intricately regulates nucleosome organization and gene expression. Histone marks also serve as binding sites for a diverse array of protein complexes and enzymes, orchestrating downstream cellular functions. Some modifications are crucial for enabling the complete activation of alternative gene expression programs in response to environmental changes. RESULTS: Our study delves into the consequences of depleting histone mark erasers, the H2B deubiquitinases Ubp8 and Ubp16, in transcription efficiency in fission yeast. Cells lacking these enzymes exhibit resistance to oxidative stress, attributed to enhanced transcription of stress genes both under basal and induced conditions. Ubp8 is recruited to stress promoters as part of the activating SAGA complex, which also acetylates histone H3, while Ubp16 promotes H2B deubiquitination in coding regions. Cells lacking Ubp8 or Ubp16 display enhanced levels of both H2Bub and H3K4me, and chromatin structure at stress genes is already affected under basal conditions and is not timely restored in the wake of elongating Pol II. Depletion of the COMPASS complex, required to methylate H3K4, solely abolishes stress resistance in Δubp16. In contrast, cells lacking Ubp8 display independence from SAGA or COMPASS for full transcriptional activation, suggesting an essential and sufficient role of H2Bub in Pol II promoter escape. CONCLUSIONS: This study provides insights into the complex histone crosstalk regulating gene expression and underscores the pivotal role of histone ubiquitination in promoting efficient nucleosome dynamics during Pol II transcription. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-025-03891-1.