The Role of RNF40 mediated H2B monoubiquitination in transcription

The Role of RNF40 mediated H2B monoubiquitination in transcription

Wanhua Xie

Doctoral thesis

Date of Examination: 2016-08-16

Date of issue: 2017-02-13

Advisor: Johnsen, Steven A. Prof. Dr.

Referee: Johnsen, Steven A. Prof. Dr.

Referee: Hahn, Heidi Prof. Dr.

Referee: Dobbelstein, Matthias Prof. Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-002B-7D3A-A

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Abstract

English

Active gene transcription is tightly correlated with the occupancy of histone H2B monoubiquitination (H2Bub1) in the transcribed region. Therefore, it is has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with its requirement for gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. We show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss. Furthermore, RNF40-suppressed genes appear to play an equally important role compared to RNF40-dependent genes in the RNF40/H2Bub1 regulatory network. We show that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks following Rnf40 deletion. Notably, genes upregulated following Rnf40 deletion, including Foxl2, are enriched for H3K27me3, which is decreased following Rnf40 deletion due to decreased expression of the Ezh2 gene. As a consequence, increased expression of some RNF40-suppressed genes is associated with enhancer activation via FOXL2. Finally, consistent with our previous findings, H2Bub1 is essential for the activation of bivalent genes, whereby RNF40, presumably via H2Bub1, modulates bivalent gene expression via coordination of the active and repressive marks H3K4me3 and H3K27me3, respectively. Together these findings show the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription dependent upon the activity of other epigenetic regulatory proteins and histone modifications.

Keywords: RNF40; H2Bub1; EZH2; H3K4me3