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Involvement of promoter/enhancers in a feedback loop to regulate human gene expression

ABSTRACT: The study described here was undertaken to extend the observation that some transcription factors can either stimulate or suppress gene expression depending on the local environment of their DNA binding site. It is suggested that if such transcription factors also had a mechanism to sense the expression level of the gene they control, then they could create a feedback loop able to keep expression of a gene within a limited range. The transcription factor would be activating if gene expression were determined to be too low and repressing if it were too high. To test the above idea, I have examined the effect of gene expression on the ability of the transcription factor binding areas, the promoter/enhancers, to stimulate or attenuate gene expression depending on the existing expression level of a gene. Studies were carried out with a population of 61 human genes expressed selectively in liver. A similar study was carried out with thyroid genes. The total length of all promoter/enhancers in each gene sequence was determined and compared in weakly and strongly expressed genes. The results showed that the level of expression was stimulated by promoter/enhancers in weakly expressed genes and antagonized in strongly expressed ones. The results are interpreted to indicate that promoter/enhancers act to keep expression of a gene within a defined range that is appropriate for the gene's function. Molecular biology; Cell biology; Genetics; Gene expression; Genomics; Human genetics; Promoter; Transcription factor; Transcription; Feedback loop; Promoter/enhancer

SUBMITTER: Brown J

PROVIDER: S-EPMC7501438 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Project description:The vitamin D receptor (VDR) mediates the endocrine actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and autoregulates the expression of its own gene in target cells. In studies herein, we used chromatin immunoprecipitation-chip analyses to examine further the activities of 1,25(OH)(2)D(3) and to assess the consequences of VDR/retinoid X receptor heterodimer binding at the VDR gene locus. We also explored mechanisms underlying the ability of retinoic acid, dexamethasone, and the protein kinase A activator forskolin to induce VDR up-regulation as well. We confirmed two previously identified intronic 1,25(OH)(2)D(3)-inducible enhancers and discovered two additional regions, one located 6 kb upstream of the VDR transcription start site. Although RNA polymerase II was present at the transcription start site in the absence of 1,25(OH)(2)D(3), it was strikingly up-regulated at both this site and at individual enhancers in its presence. 1,25(OH)(2)D(3) also increased basal levels of H4 acetylation at these enhancers as well. Surprisingly, many of these enhancers were targets for CCAAT enhancer-binding protein-beta and runt-related transcription factor 2; a subset also bound cAMP response element binding protein, retinoic acid receptor, and glucocorticoid receptor. Unexpectedly, many of these factors were resident at the Vdr gene locus in the absence of inducer, suggesting that they might contribute to basal Vdr gene expression. Indeed, small interfering RNA down-regulation of CCAAT enhancer-binding protein-beta suppressed basal VDR expression. These regulatory activities of 1,25(OH)(2)D(3), forskolin, and dexamethasone were recapitulated in MC3T3-E1 cells stably transfected with a full-length VDR bacterial artificial chromosome (BAC) clone-luciferase reporter gene. Finally, 1,25(OH)(2)D(3) also induced accumulation of VDR and up-regulated H4 acetylation at conserved regions in the human VDR gene. These data provide important new insights into VDR gene regulation in bone cells.

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Involvement of promoter/enhancers in a feedback loop to regulate human gene expression

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