Affiliation:
1. Cutaneous Biology Research Center and Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129
2. Laboratory of Development and Differentiation, Korea Research Institute of Biosciences, Daejon 305-600, South Korea
Abstract
ABSTRACT
Methylation of histone H3 at lysine 9 (H3-K9) mediates heterochromatin formation by forming a binding site for HP1 and also participates in silencing gene expression at euchromatic sites. ESET, G9a, SUV39-h1, SUV39-h2, and Eu-HMTase are histone methyltransferases that catalyze H3-K9 methylation in mammalian cells. Previous studies demonstrate that the SUV39-h proteins are preferentially targeted to the pericentric heterochromatin, and mice lacking both
Suv39-h
genes show cytogenetic abnormalities and an increased incidence of lymphoma. G9a methylates H3-K9 in euchromatin, and
G9a
null embryos die at 8.5 days postcoitum (dpc).
G9a
null embryo stem (ES) cells show altered DNA methylation in the Prader-Willi imprinted region and ectopic expression of the
Mage
genes. So far, an
Eu-HMTase
mouse knockout has not been reported. ESET catalyzes methylation of H3-K9 and localizes mainly in euchromatin. To investigate the in vivo function of
Eset
, we have generated an allele that lacks the entire pre- and post-SET domains and that expresses
lacZ
under the endogenous regulation of the
Eset
gene. We found that zygotic
Eset
expression begins at the blastocyst stage and is ubiquitous during postimplantation mouse development, while the maternal
Eset
transcripts are present in oocytes and persist throughout preimplantation development. The homozygous mutations of
Eset
resulted in peri-implantation lethality between 3.5 and 5.5 dpc. Blastocysts null for
Eset
were recovered but in less than Mendelian ratios. Upon culturing, 18 of 24
Eset
−/−
blastocysts showed defective growth of the inner cell mass and, in contrast to the ∼65% recovery of wild-type and
Eset
+/−
ES cells, no
Eset
−/−
ES cell lines were obtained. Global H3-K9 trimethylation and DNA methylation at IAP repeats in
Eset
−/−
blastocyst outgrowths were not dramatically altered. Together, these results suggest that
Eset
is required for peri-implantation development and the survival of ES cells.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
315 articles.
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