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Vol. 18, Issue 6, 2356-2366, June 2007

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

Sandra Lubitz^*, Stefan Glaser^*,, Julia Schaft^*,, A. Francis Stewart^*, and Konstantinos Anastassiadis^*,

*Genomics Group, BioInnovations Zentrum, and Centre for Regenerative Therapies Dresden, Technische Universität Dresden, 01307 Dresden, Germany

Submitted December 1, 2006; Revised March 14, 2007; Accepted March 30, 2007
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 (ES) cell lines deficient for Mll2 to examine its function more accurately. Mll2–/– ES cells are viable and retain pluripotency, but they 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. Although ectodermal delays were severe and mesodermal delays persisted at about three days, endodermal differentiation seemed 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 it contributes to the coordination and timing of early differentiation decisions.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present addresses: The Walter and Eliza Hall Institute for Medical Research, Cancer and Haematology Division, 1G Royal Parade, Parkville, Melbourne, VIC 3050, Australia;

Sydney IVF, 4 O'Connell St., Sydney 2000, Australia.

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

Abbreviations used: APC, allophycocyanin; EB, embryoid body; ES, embryonic stem; F/F, FLP-rescued; H3K4, histone 3 lysine 4; H3K27, histone 3 lysine 27; LIF, leukemia inhibitory factor; Mll, mixed lineage leukemia; PcG, Polycomb group; trxG, trithorax group.