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MBC in Press, published online ahead of print April 11, 2007
Mol. Biol. Cell 10.1091/mbc.E06-11-1060

A more recent version of this article appeared on June 1, 2007
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Submitted on December 1, 2006
Revised on March 14, 2007
Accepted on March 30, 2007

Increased Apoptosis and Skewed Differentiation in Mouse Embryonic Stem Cells Lacking the Histone Methyltransferase, Mll2

Sandra Lubitz,* Stefan Glaser,*{dagger} Julia Schaft,*{ddagger} A. Francis Stewart,* and Konstantinos Anastassiadis*{sect}

*Genomics, BioInnovationsZentrum, Technische Universität Dresden, and {sect}Centre for Regenerative Therapies Dresden, Tatzberg 47-51, 01307 Dresden, Germany

Monitoring Editor: Wendy Bickmore

Epigenetic regulation by histone methyltransferases provides transcriptional memory and inheritable propagation of gene expression patterns. Potentially the transition from a pluripotent state to lineage commitment also includes epigenetic instructions. The histone 3 lysine 4 methyltransferase, Mll2/Wbp7, is essential for embryonic development. Here we used embryonic stem cell lines deficient for Mll2 to examine its function more accurately. Mll2-/- ES cells are viable and retain pluripotency, but display cell proliferation defects due to an enhanced rate of apoptosis. Apoptosis was not relieved by caspase inhibition and correlated with decreased Bcl2 expression. Concordantly, Mll2 binds to the Bcl2 gene and H3K4me3 levels are reduced at the binding site when Mll2 is absent. In vitro differentiation showed delays along representative pathways for all three germ layers. Though ectodermal delays were severe and mesodermal delays persisted at around 3 d, endodermal differentiation appeared to recover and overshoot, concomitant with prolonged Oct4 gene expression. Hence, Mll2 is not required for ES cell self-renewal or the complex changes in gene expression involved in lineage commitment, but contributes to the coordination and timing of early differentiation decisions.

Present addresses: {dagger}The Walter and Eliza Hall Institute for Medical Research, Cancer and Haematology Division, 1G Royal Parade, Parkville, Melbourne, VIC, 3050, Australia; {ddagger}Sydney IVF, 4 O’Connell Street, Sydney 2000, Australia.

Address correspondence to: A. Francis Stewart (francis.stewart{at}biotec.tu-dresden.de)






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