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J. Biol. Chem., Vol. 277, Issue 37, 34521-34530, September 13, 2002
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From the Department of Experimental Medicine and Cancer Research,
The Hebrew University-Hadassah Medical School,
Jerusalem 91120, Israel
Oct-3/4 is the earliest expressed transcription
factor that is known to be crucial in murine pre-implantation
development. In this report we asked whether methylation participates
in controlling changes in Oct-3/4 expression
and thus may play an important role in controlling normal
embryogenesis. We show that the Oct-3/4 gene is
unmethylated from the blastula stage but undergoes de novo
methylation at 6.5 days post-coitum and remains modified in all
adult somatic tissues analyzed. Oct-3/4 remains
unmethylated in 6.25 days post-coitum epiblast cells when other
genes, such as apoAI, undergo de novo methylation. We show
that methylation of the Oct-3/4 promoter
sequence strongly compromises its ability to direct efficient
transcription. Moreover, DNA methylation inhibits basal transcription
of the endogenous Oct-3/4 gene in
vivo. We found that the Oct-3/4 gene
harbors a cis-specific demodification element that includes
the proximal enhancer sequence. This element leads to demethylation in
embryonal carcinoma cells when the sequence is initially methylated and
protects the local region from de novo methylation in
post-implantation embryos. These results indicate that in the embryo
protection from de novo methylation is not a unique feature
of imprinted or housekeeping genes that carry a CpG island, but is also
applicable to tissue-specific genes expressed during early stages of
embryogenesis. Methylation of Oct-3/4 may be
analogous to methylation of CpG islands on the inactive X
chromosome that also occurs at later stages of development.
A Unique Developmental Pattern of Oct-3/4
DNA Methylation Is Controlled by a cis-demodification
Element*
*
This work was supported by the Academy of Sciences and
Humanities fund (to Y. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Experimental
Medicine and Cancer Research, The Hebrew University-Hadassah Medical
School, Jerusalem 91120, Israel. Tel.: 972-2-6758362; Fax:
972-2-6414583; E-mail: yberg@md2.huji.ac.il.
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