RNF40 regulates gene expression in an epigenetic context-dependent manner

Wanhua Xie, Sankari Nagarajan, Simon J. Baumgart, Robyn Laura Kosinsky, Zeynab Najafova, Vijayalakshmi Kari, Magali Hennion, Daniela Indenbirken, Stefan Bonn, Adam Grundhoff, Florian Wegwitz, Ahmed Mansouri, Steven Johnsen

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 conditional Rnf40 knockout mouse embryo fibroblasts, 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, 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 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. 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.

Original languageEnglish (US)
Article number32
JournalGenome biology
Volume18
Issue number1
DOIs
StatePublished - Feb 16 2017
Externally publishedYes

Fingerprint

Epigenomics
epigenetics
gene expression
Histone Code
Gene Expression
gene
histones
Genes
genes
transcription (genetics)
gene deletion
regulatory proteins
Gene Deletion
Ligases
ubiquitin
Ubiquitin
ligases
Knockout Mice
fibroblasts
Embryonic Structures

Keywords

  • Broad H3K4me3
  • Enhancer
  • Epigenetics
  • Ezh2
  • FOXL2
  • H2Bub1
  • RNF40

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Xie, W., Nagarajan, S., Baumgart, S. J., Kosinsky, R. L., Najafova, Z., Kari, V., ... Johnsen, S. (2017). RNF40 regulates gene expression in an epigenetic context-dependent manner. Genome biology, 18(1), [32]. https://doi.org/10.1186/s13059-017-1159-5

RNF40 regulates gene expression in an epigenetic context-dependent manner. / Xie, Wanhua; Nagarajan, Sankari; Baumgart, Simon J.; Kosinsky, Robyn Laura; Najafova, Zeynab; Kari, Vijayalakshmi; Hennion, Magali; Indenbirken, Daniela; Bonn, Stefan; Grundhoff, Adam; Wegwitz, Florian; Mansouri, Ahmed; Johnsen, Steven.

In: Genome biology, Vol. 18, No. 1, 32, 16.02.2017.

Research output: Contribution to journalArticle

Xie, W, Nagarajan, S, Baumgart, SJ, Kosinsky, RL, Najafova, Z, Kari, V, Hennion, M, Indenbirken, D, Bonn, S, Grundhoff, A, Wegwitz, F, Mansouri, A & Johnsen, S 2017, 'RNF40 regulates gene expression in an epigenetic context-dependent manner', Genome biology, vol. 18, no. 1, 32. https://doi.org/10.1186/s13059-017-1159-5
Xie W, Nagarajan S, Baumgart SJ, Kosinsky RL, Najafova Z, Kari V et al. RNF40 regulates gene expression in an epigenetic context-dependent manner. Genome biology. 2017 Feb 16;18(1). 32. https://doi.org/10.1186/s13059-017-1159-5
Xie, Wanhua ; Nagarajan, Sankari ; Baumgart, Simon J. ; Kosinsky, Robyn Laura ; Najafova, Zeynab ; Kari, Vijayalakshmi ; Hennion, Magali ; Indenbirken, Daniela ; Bonn, Stefan ; Grundhoff, Adam ; Wegwitz, Florian ; Mansouri, Ahmed ; Johnsen, Steven. / RNF40 regulates gene expression in an epigenetic context-dependent manner. In: Genome biology. 2017 ; Vol. 18, No. 1.
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AU - Hennion, Magali

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AB - 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 conditional Rnf40 knockout mouse embryo fibroblasts, 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, 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 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. 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.

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