The architectural transcription factor high mobility group I(Y) participates in photoreceptor-specific gene expression

The nonhistone chromosomal proteins high mobility group I(Y) [HMG I(Y)] hav e been shown to function as architectural transcription factors facilitatin g enhanceosome formation on a variety of mammalian promoters. Specifically, they have been shown to act as a "molecular glue" mediating protein-protei n and protein- DNA contacts within the enhanceosome complex. HMG I(Y) prote ins are expressed at high levels in embryonic and transformed cells and hav e been implicated in transcriptional regulation in these cells. Terminally differentiated cells, however, have been reported to express only minimal, if any, HMG I(Y). In contrast to these observations, we show here that adul t mouse retinal photoreceptors, which are terminally differentiated cells, express high levels of these proteins. Using retinoblastoma cells as an app roximate model, we further demonstrate in transiently transfected cells tha t inhibition of HMG I(Y) expression and mutation of HMG I(Y) binding sites significantly reduce rhodopsin promoter activity. DNase I footprint analysi s indicates that HMG I protein interacts with a discrete site within the rh odopsin proximal promoter. This site overlaps with the binding site for Crx , a paired-like homeodomain transcription factor that is essential for phot oreceptor functioning and that when mutated causes several forms of human p hotoreceptor degeneration. Both biochemical and functional experiments demo nstrate that HMG I(Y) physically associate with Crx and that their interact ion with DNA is required for high-level transcription of the rhodopsin gene . These data provide the first demonstration that HMG I(Y) can be important for gene activation in terminally differentiated cells.