Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development
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.
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