Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Highlight
  • Published:

Epigenetics

Histone methylation: it's in the numbers

Nature Reviews Cancer volume 15, page 1 (2015)Cite this article

Subjects

Access through your institution
Buy or subscribe

To examine the role of DOT1L in the regulation of HOXA gene expression, Deshpande et al. sorted lineage− SCA1+ KIT+ (LSK) cells, which are enriched in haematopoietic stem cells (HSCs), from the bone marrow of mice with inducible Dot1l deletion. Chromatin immunoprecipitation (ChIP) for H3K79 monomethylation (H3K79me1), H3K79me2 or H3K79me3 in LSKs and granulocyte-macrophage progenitors (GMPs; which have low expression levels of the Hoxa7–10 cluster and Meis1) revealed that H3K79me2 and H3K79me3 levels were reduced at these loci in GMPs compared with LSKs. On examining MLL–AF9 leukaemias, they found that HOXA gene promoters had high levels of H3K79me2 and H3K79me3 and low levels of H3K79me1. This indicates that the hyperexpression of HOXA genes is driven by the conversion of H3K79me1 to H3K79me2 and H3K79me3, and that H3K79me1 is insufficient to sustain high levels of gene expression.

Next, the authors investigated how H3K79me1 conversion to higher methylation states was regulated. Having excluded a role for changes in DOT1L expression, they investigated whether a cofactor might enhance DOT1L recruitment and activity. They found that AF10 knockdown reduced H3K79me2 levels (but not H3K79me1 levels), showing that AF10 is crucial for the conversion of H3K79me1 to H3K79me2. Af10 deletion also reduced the proliferation of leukaemia cell lines with MLL fusion proteins and impaired colony formation of MLL–AF9 and MLL–AF6 transformed cells. Af10 deletion also delayed the initiation and decreased the propagation of leukaemia in secondary recipient mice of MLL–AF9 and MLL–AF6 transformed cells. Moreover, the authors found that Af10-deficient MLL–AF9 leukaemia cells showed an increased sensitivity to the DOT1L inhibitor, EPZ004777, indicating that AF10 could be an effective therapeutic target.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Deshpande, A. J. et al. AF10 reguates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell 26, 896–908 (2014)

    Article  CAS  Google Scholar 

Download references

Authors
  1. Gemma K. Alderton
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alderton, G. Histone methylation: it's in the numbers. Nat Rev Cancer 15, 1 (2015). https://doi.org/10.1038/nrc3883

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrc3883

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing