H2AK119ub1 differentially fine-tunes gene expression by modulating canonical PRC1- and H1-dependent chromatin compaction.

Polycomb repressive complex 1 (PRC1) is a key transcriptional regulator in development via modulating chromatin structure and catalyzing histone H2A ubiquitination at Lys119 (H2AK119ub1). H2AK119ub1 is one of the most abundant histone modifications in mammalian cells. However, the function of H2AK119ub1 in polycomb-mediated gene silencing remains debated. In this study, we reveal that H2AK119ub1 has two distinct roles in gene expression, through differentially modulating chromatin compaction mediated by canonical PRC1 and the linker histone H1. Interestingly, we find that H2AK119ub1 plays a positive role in transcription through interfering with the binding of canonical PRC1 to nucleosomes and therefore counteracting chromatin condensation. Conversely, we demonstrate that H2AK119ub1 facilitates H1-dependent chromatin condensation and enhances the silencing of developmental genes in mouse embryonic stem cells, suggesting that H1 may be one of several possible pathways for H2AK119ub1 in repressing transcription. These results provide insights and molecular mechanisms by which H2AK119ub1 differentially fine-tunes developmental gene expression.

[Pathogenic role of insufficiency of polycomb repressive complex in primary myelofibrosis].

Primary myelofibrosis (PMF) is characterized by the clonal expansion of megakaryocytes and myeloid cells from stem cells with abnormal cytokine expression, resulting in bone marrow fibrosis, angiogenesis, and osteosclerosis. The use of next-generation sequencing revealed that both genetic and epigenetic changes are important in the pathogenesis of PMF. Several epigenetic regulator genes, including TET2, the polycomb-related gene ASXL1, and the polycomb-group gene EZH2, have been found to be targeted by somatic gene mutations in PMF patients. Among these, loss of Ezh2 has been demonstrated to disrupt the function of the polycomb repressive complex 2, promoting the development of JAK2V617F-induced myelofibrosis in mice. In this analysis, we highlight the role of PRC dysfunction in the pathogenesis of PMF.