Metazoan Gene Expression Research Articles

Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue.

Nuclear receptors are master regulators of metazoan gene expression with crucial roles during development and in adult physiology. Fushi tarazu factor 1 (FTZ-F1) subfamily members are ancient orphan receptors with homologues from Drosophila to human that regulate diverse gene expression programs important for developmental processes, reproduction and cholesterol homeostasis in an apparently ligand-independent manner. Thus, developmental and tissue-specific cofactors may be particularly important in modulating the transcriptional activities of FTZ-F1 receptors. In Drosophila, the homeodomain protein Fushi tarazu acts as a cofactor for FTZ-F1 (NR5A3), leading to the hypothesis that a similar type of homeodomain cofactor-nuclear receptor relationship might exist in vertebrates. In this study, we have identified and characterized the homeodomain protein Prox1 as a co-repressor for liver receptor homologue 1 (LRH1/NR5A2), a master regulator of cholesterol homeostasis in mammals. Our study suggests that interactions between LRH1 and Prox1 may fulfil roles both during development of the enterohepatic system and in adult physiology of the liver.

Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs.

We propose that the microRNA milieu, unique to each cell type, productively dampens the expression of thousands of mRNAs and provides important context for the evolution of all metazoan mRNA sequences. For genes that should not be expressed in a particular cell type, protein output is lowered to inconsequential levels. For other genes, dosage is adjusted in a manner that allows for customized expression in different cell types while achieving a more uniform level within each cell type. In these ways, the microRNAs add an extensive layer of gene control that integrates with transcriptional and other regulatory processes to expand the complexity of metazoan gene expression.

A Small Domain of CBP/p300 Binds Diverse Proteins: Solution Structure and Functional Studies

The transcriptional coactivators CBP and p300 are critical regulators of metazoan gene expression. They associate with many different DNA-bound transcription factors through small, conserved domains. We have identified a compactly folded 46 residue domain in CBP and p300, the I RF-3 bi nding d omain (IBiD), and we have determined its structure by NMR. It has a helical framework containing an apparently flexible polyglutamine loop that participates in ligand binding. Spectroscopic data indicate that induced folding accompanies association of IBiD with its partners, which exhibit no evident sequence similarities. We demonstrate the significance both in vitro and in vivo of interactions between IBiD and a number of diverse partners. Thus, IBiD is an important contributor to signal integration by CBP and p300.

Transcriptional Repression by Thyroid Hormone Receptors: A ROLE FOR RECEPTOR HOMODIMERS IN THE RECRUITMENT OF SMRT COREPRESSOR

Nuclear hormone receptors, such as the thyroid hormone receptors (T3Rs) and retinoid X receptors (RXRs), are ligand-regulated transcription factors that control key aspects of metazoan gene expression. T3Rs can bind to DNA either as receptor homodimers or as heterodimers with RXRs. Once bound to DNA, nuclear hormone receptors regulate target gene expression by recruiting auxiliary proteins, denoted corepressors and coactivators. We report here that T3R homodimers assembled on DNA exhibit particularly strong interactions with the SMRT corepressor, whereas T3R.RXR heterodimers are inefficient at binding to SMRT. Mutants of T3R that exhibit enhanced repression properties, such as the v-Erb A oncoprotein or the T3Rbeta-Delta432 mutant found in human resistance to thyroid hormone syndrome, display enhanced homodimerization properties and exhibit unusually strong interactions with the SMRT corepressor. Significantly, the topology of a DNA binding site can determine whether that site recruits primarily homodimers or heterodimers and therefore whether corepressor is efficiently or inefficiently recruited to the resulting receptor-DNA complex. We suggest that T3R homodimers, and not heterodimers, may be important mediators of transcriptional repression and that the nature of the DNA binding site, by selecting for receptor homodimers or heterodimers, can influence the ability of the receptor to recruit corepressor.