Are TADs supercoiled?

Abstract

Topologically associating domains (TADs) are megabase-sized building blocks of interphase chromosomes in higher eukaryotes. TADs are chromosomal regions with increased frequency of internal interactions. On average a pair of loci separated by a given genomic distance contact each other 2–3 times more frequently when they are in the same TAD as compared to a pair of loci located in two neighbouring TADs. TADs are also functional blocks of chromosomes as enhancers and their cognate promoters are normally located in the same TAD, even if their genomic distance from each other can be as large as a megabase. The internal structure of TADs, causing their increased frequency of internal interactions, is not established yet. We survey here experimental studies investigating presence of supercoiling in interphase chromosomes. We also review numerical simulation studies testing whether transcription-induced supercoiling of chromatin fibres can explain how TADs are formed and how they can assure very efficient interactions between enhancers and their cognate promoters located in the same TAD.

Chromatin Architecture in the Fly: Living without CTCF/Cohesin Loop Extrusion?

“…An intriguing aspect of the BEAF‐32 binding sites is that they are associated with TSSs and particularly with divergent TSSs . This raises the possibility that gene orientation may be relevant to minidomain formation and a potential mechanism could involve transcription‐dependent chromatin supercoiling . A recent analysis of minidomains indicates that many represent gene loops with the interaction between the TSS and transcription termination sites (TTSs) .…”

“…[41] This raises the possibility that gene orientation may be relevant to minidomain formation and a potential mechanism could involve transcription-dependent chromatin supercoiling. [42,43] A recent analysis of minidomains indicates that many represent gene loops with the interaction between the TSS and transcription termination sites (TTSs). [44] Blocking transcription inhibits these gene loops and so does depletion of the Rad21 component of the cohesin complex, implicating cohesin, and potentially cohesin-mediated loop extrusion, in the formation of gene loop minidomains.…”

Control of RNA polymerase II promoter-proximal pausing by DNA supercoiling

“…Interestingly, long-range communication between RNA polymerases by supercoiling cancelation and interference has been recently reported in bacteria (Kim et al, 2019). In any case, the accumulation of (-) supercoiling at promoter regions seems a wide-spread characteristic of eukaryotic gene organization (Bermudez et al, 2010;Kouzine et al, 2013;Matsumoto and Hirose, 2004;Naughton et al, 2013;Teves and Henikoff, 2014), and could serve additional functions such as, for example, favoring the formation of non-B DNA structures with regulatory functions (Kouzine et al, 2004;Kouzine et al, 2008), providing an appropriate 3D conformation to favor interaction with regulatory elements (Liu et al, 2001;Racko et al, 2019) or as a means to isolate and maintain the topology of the transcriptional unit (Achar et al, 2020). Finally, the tight interdependence between chromatin structure, DNA supercoiling and topoisomerase function (Dykhuizen et al, 2013;Kaczmarczyk et al, 2020;Sperling et al, 2011;Teves and Henikoff, 2014) provides an additional level of complexity expanding the possibilities of fine-tune transcriptional regulation.…”

Mapping chromatin accessibility and active regulatory elements reveals new pathological mechanisms in human gliomas

“…Chromatin conformation may influence regulation of gene expression (Lupiáñez et al, 2015, Donaldson-Collier et al, 2019 and topologically associating domains (TADs) segregate the genome into megabase-scale regions. Enhancers and their cognate promoters are typically located in the same TAD, even if their genomic distance between them is as large as a mega-base (Racko et al, 2018). Since we were most interested in promoter-enhancer contacts that require high-resolution maps, we used published high resolution fetal brain Hi-C data to putative enhancers locations to search for potential interactions that may elicit pathogenic mechanisms.…”