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First published online 15 March 2006
doi: 10.1242/dev.02302
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1 Genomics, BioInnovationsZentrum, Dresden University of Technology, Am Tatzberg
47, Dresden 01307, Germany.
2 Department of Molecular Biology and Computational Biology Unit at BCCS,
University of Bergen, HiB, Bergen N5020, Norway.
3 National Institute for Medical Research, The Ridgeway Mill Hill, London NW7
1AA, UK.
Author for correspondence (e-mail:
stewart{at}biotec.tu-dresden.de)
Accepted 7 February 2006
Epigenesis is the process whereby the daughters of a dividing cell retain a chromatin state determined before cell division. The best-studied cases involve the inheritance of heterochromatic chromosomal domains, and little is known about specific gene regulation by epigenetic mechanisms. Recent evidence shows that epigenesis pivots on methylation of nucleosomes at histone 3 lysines 4, 9 or 27. Bioinformatics indicates that mammals have several enzymes for each of these methylations, including at least six histone 3 lysine 4 methyltransferases. To look for evidence of gene-specific epigenetic regulation in mammalian development, we examined one of these six, Mll2, using a multipurpose allele in the mouse to ascertain the loss-of-function phenotype. Loss of Mll2 slowed growth, increased apoptosis and retarded development, leading to embryonic failure before E11.5. Using chimera experiments, we demonstrated that Mll2 is cell-autonomously required. Evidence for gene-specific regulation was also observed. Although Mox1 and Hoxb1 expression patterns were correctly established, they were not maintained in the absence of Mll2, whereas Wnt1 and Otx2 were. The Mll2 loss-of-function phenotype is different from that of its sister gene Mll, and they regulate different Hox complex genes during ES cell differentiation. Therefore, these two closely related epigenetic factors play different roles in development and maintain distinct gene expression patterns. This suggests that other epigenetic factors also regulate particular patterns and that development entails networks of epigenetic specificities.
Key words: Epigenetics, Histone methylation, SET domain
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