The oct-3/4 gene

The oct genes form another important family of
regulatory genes involved in embryonic development.
Members of this family encode transcription factors
(Oct proteins), which bind to the octamer DNA sequence
ATTTGCAT in a variety of genes. The oct3 and
oct4 genes are expressed in embryonic stem cells some
time before 3.5 days after coitus and then repressed
within a few days afterwards, the exact day of repression
depending on the cell lineage. The presence or
absence of Oct-3/4 protein in developing embryonic
cells probably infl uences the fate of the cells.
The expression of the oct-3/4 gene is rapidly
down-regulated in vitro when both embryonic stem
(ES) cells and EC cells are induced to differentiate by
treatment with retinoic acid. The down-regulation
is the result of a specifi c inhibition of expression by
retinoic acid. Okazawa et al. (1991) reported that two
sequences (designated RARE1A and RARE1B) in the
oct-3 enhancer region were targets for retinoic acidmediated
repression. These sequences did not contain
a typical RAR recognition site and the loss of enhancer
activity did not involve binding of RARs.
In addition to the RARE1A/B situated in the enhancer,
a novel element has been identifi ed in the oct-3/4
gene promoter which contains a putative Sp1 binding
site juxtaposed to a DR1-type RARE (designated RAREoct)
(Pikarsky et al., 1994; Schloorlemmer et al., 1994).
Mutations in the Sp1 site drastically diminish expression
of oct-3/4 in P19 cells, showing that the binding of
an Sp1 protein or related protein is essential for maximal
activation. In the absence of retinoic acid, RAREoct
mediates transcriptional activation, but, when cells are
treated with retinoic acid, RAREoct functions as a binding
site for a negative regulator. RAREoct, being responsive
to both positive and negative regulatory proteins,
is therefore a point of integration of several signalling
pathways infl uencing oct-3/4 gene expression.
COUP-TFs have been identifi ed as candidate endogenous
repressors of the oct4 gene promoter (Schloorlemmer
et al., 1994). However, repression is exerted by
a different mechanism from the interference by COUPTFs
of retinoic acid-induced transcriptional activation
via DR1 elements, since the RAREoct is transactivated
neither by all-trans nor by 9-cis retinoic acid.
Thus, the down-regulation of oct-3/4 expression
by retinoic acid in embryonic stem cells involves two
independent mechanisms: deactivation of a stem cellspecifi
c enhancer by a mechanism not clearly defi ned
and promoter silencing by COUP orphan receptors.