RNF40 regulates gene expression in an epigenetic context-dependent manner. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Xie, Wanhua; Nagarajan, Sankari; Baumgart, Simon; Kosinsky, Robyn; Najafova, Zeynab; Kari, Vijayalakshmi; Hennion, Magali; Indenbirken, Daniela; Bonn, Stefan; Grundhoff, Adam; Wegwitz, Florian; Mansouri, Ahmed; Johnsen, Steven
• Is Part Of: Genome biology. Volume 18:Issue 1(2017)
• Page Start: 1
• Page End: 22
• Publication Date: 2017-12
• Subjects: RNF40 -- H2Bub1 -- Broad H3K4me3 -- Ezh2 -- Epigenetics -- Enhancer -- FOXL2; Genomes -- Periodicals; Biology -- Periodicals; Molecular biology -- Periodicals; 572.8633
• DOI: 10.1186/s13059-017-1159-5
• Languages: English
• ISSNs: 1474-760X

Abstract

Abstract Background Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. Results Using conditionalRnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response toRnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected byRnf40 loss. Furthermore, we find that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks. H2Bub1 promotes the broadening of H3K4me3 to increase transcriptional elongation, which together lead to increased tissue-specific gene transcription. Notably, genes upregulated followingRnf40 deletion, includingFoxl2, are enriched for H3K27me3, which is decreased followingRnf40 deletion due to decreased expression of theEzh2 gene. As a consequence, increased expression of some RNF40-"suppressed" genes is associated with enhancer activation via FOXL2. Conclusion Together these findings reveal the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription. Furthermore, we show that these effects are dependent upon the activity of other epigenetic regulatory proteins and histone modifications.