The topic [far below] discusses the “exposome” and realization that current intrumentation might provide you with the result that a chemical is “undetectable at 10–14 or 10–17 molar“, which does not rule out that as many as ~6x 109 (6,000,000,000) or ~6x 106 (6,000,000) units per liter, respectively –– might still exist in your “sample.”
The topic [immediately below] discusses the successful visualization of a transcriptional complex on the enhancer/promoter region on a DNA segment on one chromosome in a single cell. This method of instrumentation is able to “visualize all the way down” to a single unit –– albeit that “unit” is not an atom, ion or chemical –– but rather comprises several hundred proteins contained in the transcriptional complex, combined with a segment of chromosome containing additional proteins plus nucletotides in the DNA helix.
DwN
From: Nebert, Daniel (nebertdw)
Sent: Sunday, November 18, 2018 5:55 PM
Subject: Dynamic interplay visualized — between enhancer/promoter regions and gene activity
Transcriptional enhancers are short DNA fragments [5 base-pairs (bp) to 25-30 bp] that control gene expression; enhancers can be nearby “upstream” or “downstream”, inside the gene (in an intron that does not get transcribed into the final messenger RNA which then gets translated into the ultimate protein), distant (many thousands of bp of DNA away), and even on a different chromosome from the gene being controlled. It has been at least 35 years since the initial discovery of enhancer modules, but it has been amazing to me –– without distinct visualization –– that the idea of “looping” nearby (cis) or distal (trans) enhancer segments, in order to produce a (contact and) interaction with the promoter (which sits very near the upstream end of the gene) could be so extensively inferred.
A long-standing question in the field remains: how does the physical interaction between enhancers and promoters impact gene expression? Authors [see attached article & editorial] describe an imaging approach by which long-range interactions between promoters and distal enhancers, and their consequences on transcriptional output, can be monitored directly. Transcriptional enhancers in multicellular eukaryotes greatly outnumber genes. In the case of humans, estimates for the total number of enhancers exceed a million elements, compared with the estimated ~21,000 genes. Thus, each promoter-and-gene is, on average, under the control of more than ten regulatory elements.
Authors combined genome-editing and multi-color live imaging to simultaneously visualize (physically) enhancer–promoter interaction and transcription at the single-cell level in Drosophila (fly) embryos. By examining transcriptional activation of a reporter mini-gene by the endogenous even-skipped enhancers –– which are located 150,000 bp away, authors could identify three distinct topological conformational states and could measure their transition kinetics. They demonstrated that sustained proximity of the enhancer to its target is required for activation. Transcription, in turn, affects the three-dimensional topology –– as it enhances the temporal stability of the proximal conformation, and is then associated with further spatial compaction. Moreover, the facilitated long-range activation results in transcriptional competition at the genetic locus, causing corresponding developmental defects. This novel approach offers quantitative insight into the spatial and temporal determinants of long-range gene regulation and their implications for cellular fates. Awesome. Simply awesome.
DwN
Nat Genet Oct 2o18; 50: 1296–1303 [article] & pp 1205–1206 [News‘N‘Views]
The topic [far below] discusses the “exposome” and realization that current intrumentation might provide you with the result that a chemical is “undetectable at 10–14 or 10–17 molar“, which does not rule out that as many as ~6x 109 (6,000,000,000) or ~6x 106 (6,000,000) units per liter, respectively –– might still exist in your “sample.”
The topic [immediately below] discusses the successful visualization of a transcriptional complex on the enhancer/promoter region on a DNA segment on one chromosome in a single cell. This method of instrumentation is able to “visualize all the way down” to a single unit –– albeit that “unit” is not an atom, ion or chemical –– but rather comprises several hundred proteins contained in the transcriptional complex, combined with a segment of chromosome containing additional proteins plus nucletotides in the DNA helix.
DwN
The topic [far below] discusses the “exposome” and realization that current intrumentation might provide you with the result that a chemical is “undetectable at 10–14 or 10–17 molar“, which does not rule out that as many as ~6x 109 (6,000,000,000) or ~6x 106 (6,000,000) units per liter, respectively –– might still exist in your “sample.”
The topic [immediately below] discusses the successful visualization of a transcriptional complex on the enhancer/promoter region on a DNA segment on one chromosome in a single cell. This method of instrumentation is able to “visualize all the way down” to a single unit –– albeit that “unit” is not an atom, ion or chemical –– but rather comprises several hundred proteins contained in the transcriptional complex, combined with a segment of chromosome containing additional proteins plus nucletotides in the DNA helix.
DwN
COMMENT: But –– Atomic microscopes have been around for decades that can view a single atom. Good point. Sorry that I wasn’t clearer; I should’ve qualified this “thought for the day” that I was thinking of “inside living, functioning cells or organisms.” In the case of single atoms, ions or molecules –– there might be a million or a billion ‘units’ below the level of detection (in any living cell or organism), whereas one large ‘unit’ (of the transcriptional process or event, viewing the enhancer-promoter complex, as it turns on a gene’s activity) can be be followed dynamically, i.e. to measure kinetics and distinguish four distinct stages, as a function of time.