The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.
BACKGROUND
Histone methylation is thought to be central to the epigenetic mechanisms that maintain and confine cellular identity in multi-cellular organisms. To examine epigenetic roles in cellular homeostasis, we conditionally mutated the histone 3 lysine 4 methyltransferase, Mll2, in embryonic stem (ES) cells, during development and in adult mice using tamoxifen-induced Cre recombination.


RESULTS
In ES cells, expression profiling unexpectedly revealed that only one gene, Magoh2, is dependent upon Mll2 and few other genes were affected. Loss of Mll2 caused loss of H3K4me3 at the Magoh2 promoter and concomitant gain of H3K27me3 and DNA methylation. Hence Mll2, which is orthologous to Drosophila Trithorax, is required to prevent Polycomb-Group repression of the Magoh2 promoter, and repression is further accompanied by DNA methylation. Early loss of Mll2 in utero recapitulated the embryonic lethality found in Mll2-/- embryos. However, loss of Mll2 after E11.5 produced mice without notable pathologies. Hence Mll2 is not required for late development, stem cells or homeostasis in somatic cell types. However it is required in the germ cell lineage. Spermatogenesis was lost upon removal of Mll2, although spermatogonia A persisted.


CONCLUSIONS
These data suggest a bimodal recruit and maintain model whereby Mll2 is required to establish certain epigenetic decisions during differentiation, which are then maintained by redundant mechanisms. We also suggest that these mechanisms relate to the epigenetic maintenance of CpG island promoters.
Genomics, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.|The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Stefan
S
Glaser
Genomics, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.|Centre for Regenerative Therapies Dresden, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.
Sandra
S
Lubitz
Monash Institute of Medical Research, Monash University, Melbourne and ARC Centre of Excellence in Biotechnology and Development, Australia.
Kate L
KL
Loveland
Department of Histology and Cell Biology, School of Medicine, Yokohama City University, Yokohama, Japan.
Kazu
K
Ohbo
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Lorraine
L
Robb
TaconicArtemis Pharmaceuticals GmbH, Neurather Ring, 51063 Cologne, Germany.|University of Applied Science Gelsenkirchen, Department of Applied Natural Sciences, August-Schmidt-Ring, 45665 Recklinghausen, Germany.
Frieder
F
Schwenk
TaconicArtemis Pharmaceuticals GmbH, Neurather Ring, 51063 Cologne, Germany.
Jost
J
Seibler
Genomics, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.
Daniela
D
Roellig
Genomics, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.
Andrea
A
Kranz
Centre for Regenerative Therapies Dresden, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.
Konstantinos
K
Anastassiadis
Genomics, BioInnovationsZentrum, Technische Universitaet Dresden, Am Tatzberg, 01307 Dresden, Germany.
A Francis
AF
Stewart