Gene silencing by nuclear orphan receptors.
Nuclear orphan receptors represent a large and diverse subgroup in the nuclear receptor superfamily. Although putative ligands for these orphan members remain to be identified, some of these receptors possess intrinsic activating, inhibitory, or dual regulatory functions in development, differentiation, homeostasis, and reproduction. In particular, gene-silencing events elicited by chicken ovalbumin upstream promoter-transcription factors (COUP-TFs); dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1); germ cell nuclear factor (GCNF); short heterodimer partner (SHP); and testicular receptors 2 and 4 (TR2 and TR4) are among the best characterized. These orphan receptors are critical in controlling basal activities or hormonal responsiveness of numerous target genes. They employ multiple and distinct mechanisms to mediate target gene repression. Complex cross-talk exists between these orphan receptors at their cognate DNA binding elements and an array of steroid?nonsteroid hormone receptors, other transcriptional activators, coactivators and corepressors, histone modification enzyme complexes, and components of basal transcriptional components. Therefore, perturbation induced by these orphan receptors at multiple levels, including DNA binding activities, receptor homo- or heterodimerization, recruitment of cofactor proteins, communication with general transcriptional machinery, and changes at histone acetylation status and chromatin structures, may contribute to silencing of target gene expression in a specific promoter or cell-type context. Moreover, the findings derived from gene-targeting studies have demonstrated the significance of these orphan receptors' function in physiologic settings. Thus, COUP-TFs, DAX-1, GCNF, SHP, and TR2 and 4 are known to be required for multiple physiologic and biologic functions, including neurogenesis and development of the heart and vascular system steroidogenesis and sex determination, gametogenesis and embryonic development, and cholesterol?lipid homeostasis.
Zhang
Ying
Y
Section on Molecular Endocrinology, Endocrinology, and Reproduction Research Branch, National Institutes of Health, Bethesda, Maryland 20892, USA.
Dufau
Maria L
ML
D000818:Animals; D051838:COUP Transcription Factor I; D051836:COUP Transcription Factors; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000378:metabolism; D005718:Gametogenesis / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051838:COUP Transcription Factor I; D051836:COUP Transcription Factors; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; C539822:NR2C1 protein, human; C490515:NR2C2 protein, human; C497589:NR2F1 protein, human; C539950:NR6A1 protein, human; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2