The role of H2B monoubiquitination in cellular differentiation

Abstract

Histones, subjected to post-translational modifications, are important regulators of the cellular processes. One of these modifications is monoubiquitination of histone H2B (H2Bub1). H2Bub1 is associated with the actively transcribed genes. Moreover, H2Bub1 is required for the proper DNA repair and was recently reported to be lost during tumor progression. The levels of H2Bub1 in the cell are tightly regulated. In mammals, ubiquitination is mediated by the E3 ubiquitin ligase RNF20/40. Another important upstream regulator of H2Bub1 is the CDK9 enzyme that promotes transcriptional elongation. It, together with an adaptor protein WAC, facilitates the RNF20/40 recruitment to the chromatin. Differentiation of the cell is a process that results in cellular specialization and acquiring a physiological function. It is accompanied by the significant changes in gene expression and in histone modification patterns. This project aimed to understand the role of H2Bub1 in cellular differentiation. Investigating human mesenchymal stem cells (hMSCs) it was observed that the H2Bub1 levels increase during differentiation into osteoblasts and adipocytes. Depletion of the H2Bub1 regulators RNF40, WAC and CDK9 resulted in inhibition of the hMSC differentiation suggesting that H2Bub1 is required for the correct progression of this process. Mechanistically, H2Bub1 was shown to participate in the activation of the “bivalent” genes that carry activatory and inhibitory histone marks. H2Bub1 deposition is required for removal of the repressive H3K27me3 from the differentiation-dependent genes. Taken together, these observations for the first time demonstrate the involvement of H2Bub1 in cellular differentiation. The proposed model suggests that H2Bub1 executes its function via promoting the resolution of bivalency on the differentiation-specific genes. These results give additional insights into H2Bub1 function during transcription of the certain subsets of genes. The obtained knowledge increases our understanding of the transcriptional regulation, carcinogenesis and stem cell biology.