RETINOIC ACID AND METHYLATION CIS-REGULATORY ELEMENTS CONTROL THE MOUSE-TISSUE NONSPECIFIC ALKALINE-PHOSPHATASE GENE-EXPRESSION

To understand the mechanisms regulating the tissue non-specific alkali ne phosphatase (TNAP) activity during development, we characterized ci s-transcriptional regulatory elements. In embryonic cells and tissues, TNAP expression was driven preferentially by the exon 1A(E1A) promote r, one of the two promoters previously defined. Transcriptional activi ty of E1A promoter was up-regulated by retinoic acid (RA) through a pu tative RA-responsive element. Transgenic mice analysis with lacZ repor ter constructs revealed negative regulatory elements within 8.5 kb of ElA promoter. Promoter sequences of endogenous TNAP in non-expressing tissues and those carried by the 8.5 kb-lacZ transgene were found to b e highly methylated. A 1 kb fragment of E1A promoter increased the met hylation level of lacZ and promoter sequences. The role of RA and DNA methylation in defining the embryonic expression pattern of TNAP is di scussed.