title: The architectural transcription factor high mobility group I(Y) participates in photoreceptor-specific gene expression.
abstract: The nonhistone chromosomal proteins high mobility group I(Y) [HMG I(Y)] have been shown to function as architectural transcription factors facilitating enhanceosome formation on a variety of mammalian promoters. Specifically, they have been shown to act as a "molecular glue" mediating protein-protein and protein-DNA contacts within the enhanceosome complex. HMG I(Y) proteins are expressed at high levels in embryonic and transformed cells and have 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 adult mouse retinal photoreceptors, which are terminally differentiated cells, express high levels of these proteins. Using retinoblastoma cells as an approximate model, we further demonstrate in transiently transfected cells that inhibition of HMG I(Y) expression and mutation of HMG I(Y) binding sites significantly reduce rhodopsin promoter activity. DNase I footprint analysis indicates that HMG I protein interacts with a discrete site within the rhodopsin proximal promoter. This site overlaps with the binding site for Crx, a paired-like homeodomain transcription factor that is essential for photoreceptor functioning and that when mutated causes several forms of human photoreceptor degeneration. Both biochemical and functional experiments demonstrate that HMG I(Y) physically associate with Crx and that their interaction 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.
authors.affiliation: The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: K Y
authors.initials: KY
authors.lastname: Chau
authors.forename: N
authors.initials: N
authors.lastname: Munshi
authors.forename: A
authors.initials: A
authors.lastname: Keane-Myers
authors.forename: K W
authors.initials: KW
authors.lastname: Cheung-Chau
authors.forename: A K
authors.initials: AK
authors.lastname: Tai
authors.forename: G
authors.initials: G
authors.lastname: Manfioletti
authors.forename: C K
authors.initials: CK
authors.lastname: Dorey
authors.forename: D
authors.initials: D
authors.lastname: Thanos
authors.forename: D J
authors.initials: DJ
authors.lastname: Zack
authors.forename: S J
authors.initials: SJ
authors.lastname: Ono
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation; D018983:DNA Footprinting; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D025741:HMGA1a Protein; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D016297:Mutagenesis, Site-Directed; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding; D012313:RNA / Q000096:biosynthesis; D016372:RNA, Antisense / Q000494:pharmacology; D012045:Regulatory Sequences, Nucleic Acid; D012160:Retina / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism; D012243:Rhodopsin / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D016372:RNA, Antisense; D015534:Trans-Activators; D014157:Transcription Factors; C109288:cone rod homeobox protein; D025741:HMGA1a Protein; D049452:Green Fluorescent Proteins; D012313:RNA; D012243:Rhodopsin