The continually renewing epithelium of the intestinal tract arises from the visceral endoderm by a series of complex developmental transitions. The mechanisms that establish and maintain the processes of cellular renewal, cell lineage allocation, and tissue restriction and spatial assignment of gene expression in this epithelium are unknown. An understanding of the regulation of intestine-specific gene regulation may provide information on the molecular mechanisms that direct these processes. In this regard, we show that intestine-specific transcription of sucrase-isomaltase, a gene that is expressed exclusively in differentiated enterocytes, is dependent on binding of a tissue-specific homeodomain protein (mouse Cdx-2) to an evolutionarily conserved promoter element in the sucrase-isomaltase gene. This protein is a member of the caudal family of homeodomain genes which appear to function in early developmental events in Drosophila melanogaster, during gastrulation in many species, and in intestinal endoderm. Unique for this homeodomain gene family, we show that mouse Cdx-2 binds as a dimer to its regulatory element and that dimerization in vitro is dependent on redox potential. These characteristics of the interaction of Cdx-2 with its regulatory element provide for a number of potential mechanisms for transcriptional regulation. Taken together, these findings suggest that members of the Cdx gene family play a fundamental role both in the establishment of the intestinal phenotype during development and in maintenance of this phenotype via transcriptional activation of differentiated intestinal genes.

A homeodomain protein related to caudal regulates intestine-specific gene transcription.

Pbx cofactors are implicated to play important roles in modulating the DNA-binding properties of heterologous homeodomain proteins, including class I Hox proteins. To assess how Pbx proteins influence Hox DNA-binding specificity, we used a binding-site selection approach to determine high-affinity target sites recognized by various Pbx-Hox homeoprotein complexes. Pbx-Hox heterodimers preferred to bind a bipartite sequence 5'-ATGATTNATNN-3' consisting of two adjacent half sites in which the Pbx component of the heterodimer contacted the 5' half (ATGAT) and the Hox component contacted the more variable 3' half (TNATNN). Binding sites matching the consensus were also obtained for Pbx1 complexed with HoxA10, which lacks a hexapeptide but requires a conserved tryptophan-containing motif for cooperativity with Pbx. Interactions with Pbx were found to play an essential role in modulating Hox homeodomain amino-terminal arm contact with DNA in the core of the Hox half site such that heterodimers of different compositions could distinguish single nucleotide alterations in the Hox half site both in vitro and in cellular assays measuring transactivation. When complexed with Pbx, Hox proteins B1 through B9 and A10 showed stepwise differences in their preferences for nucleotides in the Hox half site core (TTAT to TGAT, 5' to 3') that correlated with the locations of their respective genes in the Hox cluster. These observations demonstrate previously undetected DNA-binding specificity for the amino-terminal arm of the Hox homeodomain and suggest that different binding activities of Pbx-Hox complexes are at least part of the position-specific activities of the Hox genes.

Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus.

https://www.cell.com/cell/pdf/0092-8674(94)90526-6.pdf

extradenticle Raises the DNA binding specificity of homeotic selector gene products

Thecontinually renewing epithelium oftheintestinal tract arises fromthevisceral endoderm bya series of complex developmental transitions. Themechanisms thatestablish andmaintain theprocessesofcellular renewal, celllineage allocation, andtissue restriction andspatial assignment ofgene expression inthis epithelium areunknown. Anunderstanding oftheregulation ofintestine-specific generegulation may provide information on themolecular mechanisms thatdirect these processes.Inthisregard, we showthat intestine-specific transcription ofsucrase-isomaltase, a gene thatisexpressed exclusively indifferentiated enterocytes, isdependent on binding ofa tissue-specific homeodomain protein (mouseCdx-2)to an evolutionarily conserved promoterelement inthesucrase-isomaltase gene.Thisprotein isa memberofthe caudal family ofhomeodomain geneswhich appear tofunction inearly developmental eventsinDrosophila melanogaster, during gastrulation inmany species, andinintestinal endoderm. Unique forthis homeodomain genefamily, we showthat mouse Cdx-2binds asadimer toits regulatory element andthat dimerization invitro isdependent on redoxpotential. Thesecharacteristics oftheinteraction ofCdx-2withitsregulatory element provide fora numberofpotential mechanisms fortranscriptional regulation. Takentogether, these findings suggest that membersoftheCdxgenefamily play afundamental role bothintheestablishment oftheintestinal phenotype duringdevelopment andinmaintenance ofthisphenotype viatranscriptional activation of differentiated intestinal genes.

A Homeodomain Protein Related tocaudal Regulates Intestine-Specif ic GeneTranscription

Distant liaisons: long-range enhancer-promoter interactions in Drosophila.

Cooperativity in binding of regulatory proteins to multiple DNA sites can heighten the sensitivity and specificity of the transcriptional response. We report here the cooperative DNA-binding properties of a developmentally active regulatory protein encoded by the Drosophila homeotic gene Ultrabithorax (Ubx). We show that naturally occurring binding sites for the Ubx-encoded protein contain clusters of multiple individual binding site sequences. Such sites can form complexes containing a dozen or more Ubx-encoded protein molecules, with simultaneous cooperative interactions between adjacent and distant DNA sites. The distant mode of interaction involves a DNA looping mechanism; both modes appear to enhance transcriptional activation in a simple yeast assay system. We found that cooperative binding is dependent on sequences outside the homeodomain, and we have identified regions predicted to form coiled coils carboxy terminal to the homeodomains of the Ubx-encoded protein and several other homeotic proteins. On the basis of our findings, we propose a multisite integrative model of homeotic protein action in which functional regulatory elements can be built from a few high-affinity sites, from many lower-affinity sites, or from sites of some intermediate number and affinity. An important corollary of this model is that even small differences in binding of homeotic proteins to individual sites could be summed to yield large overall differences in binding to multiple sites. This model is consistent with reports that homeodomain protein targets contain multiple individual binding site sequences distributed throughout sizable DNA regions. Also consistent is a recent report that sequences carboxy terminal to the Ubx homeodomain can contribute to segmental specificity.

Cooperative binding of an Ultrabithorax homeodomain protein to nearby and distant DNA sites.

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Cooperative binding of an Ultrabithorax homeodomain protein to nearby and distant DNA sites.