Why the activity of a gene depends on its neighbors

Feuerborn, Alexander; Cook, Peter R.

doi:10.1016/j.tig.2015.07.001

Cited by 82 publications

(71 citation statements)

References 75 publications

(100 reference statements)

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“…The greater than twofold increase in transcription from a tandem duplicate could arise from aspects of various known regulatory mechanisms. Some of the possibilities we can envision include the following: (i) more frequent rebinding of transcription factors because the local concentration of binding sites is higher in tandemly arranged duplicates (18); (ii) more efficient looping of DNA due to clusters of transcription factors binding to identical sites on both gene copies (18); or (iii) more effective remodeling of chromatin to a favorable state for transcription (19). Any of these mechanisms could be enhanced or attenuated by neighboring sequences (i.e., by classical position effects), which could account for the observed dependence of the degree of overactivity on chromosomal position.…”

Section: The Biological Significance and Potential Mechanisms Underlyingmentioning

confidence: 99%

Expression of tandem gene duplicates is often greater than twofold

Loehlin

Carroll

2016

Proc. Natl. Acad. Sci. U.S.A.

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Tandem gene duplication is an important mutational process in evolutionary adaptation and human disease. Hypothetically, two tandem gene copies should produce twice the output of a single gene, but this expectation has not been rigorously investigated. Here, we show that tandem duplication often results in more than double the gene activity. A naturally occurring tandem duplication of the Alcohol dehydrogenase (Adh) gene exhibits 2.6-fold greater expression than the single-copy gene in transgenic Drosophila. This tandem duplication also exhibits greater activity than two copies of the gene in trans, demonstrating that it is the tandem arrangement and not copy number that is the cause of overactivity. We also show that tandem duplication of an unrelated synthetic reporter gene is overactive (2.3- to 5.1-fold) at all sites in the genome that we tested, suggesting that overactivity could be a general property of tandem gene duplicates. Overactivity occurs at the level of RNA transcription, and therefore tandem duplicate overactivity appears to be a previously unidentified form of position effect. The increment of surplus gene expression observed is comparable to many regulatory mutations fixed in nature and, if typical of other genomes, would shape the fate of tandem duplicates in evolution.

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Section: The Biological Significance and Potential Mechanisms Underlyingmentioning

confidence: 99%

Expression of tandem gene duplicates is often greater than twofold

Loehlin

Carroll

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…As a result of TSS-Seq, OC-Seq, and other epigenetic studies in animals, a new paradigm for understanding the structure of promoter regions is starting to emerge in the literature which posits that the classical binary division into core versus distal promoter regions is an oversimplification that no longer aligns well with the totality of current findings, particularly in vertebrates (reviewed in Andersson, 2015;Feuerborn and Cook, 2015;Kim and Shiekhattar, 2015). In particular, it is clear that the presence of one or more previously labeled CPEs within a promoter is not an absolute requirement in order to achieve basal transcription (Kim and Shiekhattar, 2015) and that the structure of regions that function as a "promoter" and the structure of regions that function as an "enhancer" is essentially identical for many human and mouse loci.…”

Section: The State Of the Core: Our Limited Knowledge Of Pol II Core mentioning

confidence: 99%

Small Genetic Circuits and MicroRNAs: Big Players in Polymerase II Transcriptional Control in Plants

et al. 2016

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ORCID IDs: 0000-0001-6793-6151 (M.M.); 0000-0002-0105-6431 (S.A.F.)RNA Polymerase II (Pol II) regulatory cascades involving transcription factors (TFs) and their targets orchestrate the genetic circuitry of every eukaryotic organism. In order to understand how these cascades function, they can be dissected into small genetic networks, each containing just a few Pol II transcribed genes, that generate specific signal-processing outcomes. Small RNA regulatory circuits involve direct regulation of a small RNA by a TF and/or direct regulation of a TF by a small RNA and have been shown to play unique roles in many organisms. Here, we will focus on small RNA regulatory circuits containing Pol II transcribed microRNAs (miRNAs). While the role of miRNA-containing regulatory circuits as modular building blocks for the function of complex networks has long been on the forefront of studies in the animal kingdom, plant studies are poised to take a lead role in this area because of their advantages in probing transcriptional and posttranscriptional control of Pol II genes. The relative simplicity of tissue-and cell-type organization, miRNA targeting, and genomic structure make the Arabidopsis thaliana plant model uniquely amenable for small RNA regulatory circuit studies in a multicellular organism. In this Review, we cover analysis, tools, and validation methods for probing the component interactions in miRNA-containing regulatory circuits. We then review the important roles that plant miRNAs are playing in these circuits and summarize methods for the identification of small genetic circuits that strongly influence plant function. We conclude by noting areas of opportunity where new plant studies are imminently needed.

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“…Clustering around the strongest enhancers would allow a large number of genes to benefit the increase in expression. Finally, in the third scenario, the transcription of a gene directly stimulates its neighbors (Feuerborn et al 2015). Clustering would then directly increase transcription at a local scale.…”

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confidence: 99%

Clustering of Drosophila housekeeping promoters facilitates their expression

et al. 2017

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Housekeeping genes of animal genomes cluster in the same chromosomal regions. It has long been suggested that this organization contributes to their steady expression across all the tissues of the organism. Here, we show that the activity of Drosophila housekeeping gene promoters depends on the expression of their neighbors. By measuring the expression of ∼85,000 reporters integrated in Kc167 cells, we identified the best predictors of expression as chromosomal contacts with the promoters and terminators of active genes. Surprisingly, the chromatin composition at the insertion site and the contacts with enhancers were less informative. These results are substantiated by the existence of genomic "paradoxical" domains, rich in euchromatic features and enhancers, but where the reporters are expressed at low level, concomitant with a deficit of interactions with promoters and terminators. This indicates that the proper function of housekeeping genes relies not on contacts with long distance enhancers but on spatial clustering. Overall, our results suggest that spatial proximity between genes increases their expression and that the linear architecture of the Drosophila genome contributes to this effect.

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Why the activity of a gene depends on its neighbors

Cited by 82 publications

References 75 publications

Expression of tandem gene duplicates is often greater than twofold

Expression of tandem gene duplicates is often greater than twofold

Small Genetic Circuits and MicroRNAs: Big Players in Polymerase II Transcriptional Control in Plants

Clustering of Drosophila housekeeping promoters facilitates their expression

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