3DQuant · Understanding long-range transcriptional regulation in the context of the 3D genome organization

Understanding long-range transcriptional regulation in the context of the 3D genome organization

Enhancers are DNA sequences elements that in metazoans modulate transcription of a target promoter from (often very large) genomic distances1-3. Such type of long-range regulation is thought to arise from the formation of chromosome loops enabling physical interactions between an enhancer and its cognate promoter3,4. However, how specific patterns physical interactions between enhancers and promoters are established, and how regulatory information is relayed is still unclear. Recent studies have shown that the structure of mammalian chromosomes is partitioned into consecutive self-associating domains called Topologically Associating Domains (TADs)5-7. TADs not only constitute a unit of chromosome folding but, as shown by many functional studies, coincide with regulatory domains where enhancer function is constrained to certain sets of promoters8,9. Studying how the chromatin fiber folds within the nucleus and how structures such as TADs influence gene regulation has become the focus of many research groups not only for its relevance in fundamental scientific research but also because it relates to the genetic disorders10,11. Several studies have indeed shown that defects in chromatin structure that impact enhancer-promoter interactions are responsible for the onset of some genetic disorders. Yet how TADs are able to modulate enhancer action, and thus long-range transcription, is still unknown and quantitative studies dissecting the importance of this structure for the enhancer function are still missing. Our main goal was to determine the quantitative relationship between the three-dimensional (3D) chromatin architecture (and namely the presence of TADs) and promoter activity to unravel the mechanism of long-range transcriptional modulation mediated by enhancers. Our first objective was to establish a mouse embryonic stem cell (mESC) system enabling to measure promoter-enhancer physical interactions and gene activity in parallel and in a quantitative manner, in an environment devoid of additional regulatory or structural interactions. By using this system our main goals were to assess how TADs influence the action of the enhancer on its cognate promoter as well as to explore how fluctuations in enhancer-promoter interactions impact cell-to-cell and temporal transcriptional variability. References: 1. Visel A, et al. Nature 457:854-858 (2009) 2. Visel A, et al. Nature 461:199-205 (2009) 3. Lettice LA, et al. Hum Mol Genet 12:1725-1735 (2003) 4. Sanyal A, et al. Nature 489:109-113 (2012) 5. Dixon JR, et al. Nature 485:376-380 (2012) 6. Nora EP, et al. Nature 485:381-385 (2012) 7. Sexton T, et al. Cell 148:458-472 (2012) 8. Shen Y, et al. Nature 488:116-120 (2012) 9. Symmons O, et al. Genome Res 24:390-400 (2014) 10. Lupianez DG, et al. Cell 161:1012-1025 (2015) 11. Kragesteen BK, et al. Nat Genet 50:1463-1473 (2018)

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