CoChat
Sign Up
Cited by 188Genomics and Chromatin DynamicsGene Regulatory Network AnalysisDevelopmental Biology and Gene Regulation

Transcriptional coupling of distant regulatory genes in living embryos

Open access
Levo, Michal, Raimundo, João, Bing, Xin Yang, Sisco, Zachary, Batut, Philippe J., Ryabichko, Sergey, Gregor, Thomas, Levine, Michael S.·2022·Nature
DOI 10.1038/s41586-022-04680-7PMC PMC9886134
Open this paper in CoChat — free account

Abstract

The prevailing view of metazoan gene regulation is that individual genes are independently regulated by their own dedicated sets of transcriptional enhancers. Past studies have reported long-range gene-gene associations 1-3, but their functional importance in regulating transcription remains unclear. Here we used quantitative single-cell live imaging methods to provide a demonstration of co-dependent transcriptional dynamics of genes separated by large genomic distances in living Drosophila embryos. We find extensive physical and functional associations of distant paralogous genes, including co-regulation by shared enhancers and co-transcriptional initiation over distances of nearly 250 kilobases. Regulatory interconnectivity depends on promoter-proximal tethering elements, and perturbations in these elements uncouple transcription and alter the bursting dynamics of distant genes, suggesting a role of genome topology in the formation and stability of co-transcriptional hubs. Transcriptional coupling is detected throughout the fly genome and encompasses a broad spectrum of conserved developmental processes, suggesting a general strategy for long-range integration of gene activity.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41586-022-04680-7

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A recent study in Drosophila has identified elements that are not enhancers but are thought to facilitate interactions between regulatory elements by tethering them together.

    “A recent study in Drosophila has identified what may be similar elements, which are not enhancers but are thought to facilitate interactions between regulatory elements by tethering them together.63”

    From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [63]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 57

  1. [1]Schoenfelder S. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nat Genet 42, 53– 61, doi: 10.1038/ng.496 (2010). 20010836 PMC3237402 · DOI
  2. [2]Li G. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84– 98, doi: 10.1016/j.cell.2011.12.014 (2012). 22265404 PMC3339270 · DOI · Paper page
  3. [4]Jacob F. & Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 3, 318– 356, doi: 10.1016/s0022-2836(61)80072-7 (1961). 13718526 · DOI
  4. [5]Long HK, Prescott SL & Wysocka J. Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution. Cell 167, 1170– 1187, doi: 10.1016/j.cell.2016.09.018 (2016). 27863239 PMC5123704 · DOI · Paper page
  5. [7]Furlong EEM & Levine M. Developmental enhancers and chromosome topology. Science 361, 1341– 1345, doi: 10.1126/science.aau0320 (2018). 30262496 PMC6986801 · DOI · Paper page
  6. [8]Lunde K, Biehs B, Nauber U. & Bier E. The knirps and knirps-related genes organize development of the second wing vein in Drosophila. Development 125, 4145– 4154 (1998). 9753669
  7. [9]Scuderi A, Simin K, Kazuko SG, Metherall JE & Letsou A. scylla and charybde, homologues of the human apoptotic gene RTP801, are required for head involution in Drosophila. Dev Biol 291, 110– 122, doi: 10.1016/j.ydbio.2005.12.014 (2006). 16423342 · DOI
  8. [10]Cheng Y. Co-regulation of invected and engrailed by a complex array of regulatory sequences in Drosophila. Dev Biol 395, 131– 143, doi: 10.1016/j.ydbio.2014.08.021 (2014). 25172431 PMC4189978 · DOI
  9. [11]Stathopoulos A, Tam B, Ronshaugen M, Frasch M. & Levine M. pyramus and thisbe: FGF genes that pattern the mesoderm of Drosophila embryos. Genes Dev 18, 687– 699, doi: 10.1101/gad.1166404 (2004). 15075295 PMC387243 · DOI
  10. [12]Rothe M, Wimmer EA, Pankratz MJ, González-Gaitán M. & Jäckle H. Identical transacting factor requirement for knirps and knirps-related gene expression in the anterior but not in the posterior region of the Drosophila embryo. Mechanisms of Development 46, 169– 181, doi: 10.1016/0925-4773(94)90069-8 (1994). 7918102 · DOI
  11. [13]Zinani OQH, Keseroğlu K, Ay A. & Özbudak EM Pairing of segmentation clock genes drives robust pattern formation. Nature 589, 431– 436, doi: 10.1038/s41586-020-03055-0 (2021). 33361814 PMC7932681 · DOI
  12. [14]Michalak P. Coexpression, coregulation, and cofunctionality of neighboring genes in eukaryotic genomes. Genomics 91, 243– 248, doi: 10.1016/j.ygeno.2007.11.002 (2008). 18082363 · DOI
  13. [15]Tomancak P. Global analysis of patterns of gene expression during Drosophila embryogenesis. Genome Biol 8, R145, doi: 10.1186/gb-2007-8-7-r145 (2007). 17645804 PMC2323238 · DOI
  14. [16]Hammonds AS Spatial expression of transcription factors in Drosophila embryonic organ development. Genome Biol 14, R140, doi: 10.1186/gb-2013-14-12-r140 (2013). 24359758 PMC4053779 · DOI
  15. [17]Hsieh T-HS Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding. Molecular Cell 78, 539– 553.e538, doi: 10.1016/j.molcel.2020.03.002 (2020). 32213323 PMC7703524 · DOI · Paper page
  16. [19]Rowley MJ Analysis of Hi-C data using SIP effectively identifies loops in organisms from C. elegans to mammals. Genome Res 30, 447– 458, doi: 10.1101/gr.257832.119 (2020). 32127418 PMC7111518 · DOI
  17. [20]Cusanovich DA The cis-regulatory dynamics of embryonic development at single-cell resolution. Nature 555, 538– 542, doi: 10.1038/nature25981 (2018). 29539636 PMC5866720 · DOI · Paper page
  18. [21]Gaskill MM, Gibson TJ, Larson ED & Harrison MM GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo. eLife 10, doi: 10.7554/elife.66668 (2021). PMC8079149 33720012 · DOI
  19. [22]Fukaya T, Lim B. & Levine M. Enhancer Control of Transcriptional Bursting. Cell 166, 358– 368, doi: 10.1016/j.cell.2016.05.025 (2016). 27293191 PMC4970759 · DOI · Paper page
  20. [23]Chen H. Dynamic interplay between enhancer–promoter topology and gene activity. Nature Genetics 50, 1296– 1303, doi: 10.1038/s41588-018-0175-z (2018). 30038397 PMC6119122 · DOI · Paper page
  21. [24]Garcia HG, Tikhonov M, Lin A. & Gregor T. Quantitative imaging of transcription in living Drosophila embryos links polymerase activity to patterning. Curr Biol 23, 2140– 2145, doi: 10.1016/j.cub.2013.08.054 (2013). 24139738 PMC3828032 · DOI
  22. [26]Benabdallah NS Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation. Molecular Cell 76, 473– 484.e477, doi: 10.1016/j.molcel.2019.07.038 (2019). 31494034 PMC6838673 · DOI · Paper page
  23. [27]Calhoun VC, Stathopoulos A. & Levine M. Promoter-proximal tethering elements regulate enhancer-promoter specificity in the Drosophila Antennapedia complex. Proc Natl Acad Sci U S A 99, 9243– 9247, doi: 10.1073/pnas.142291299 (2002). 12093913 PMC123125 · DOI
  24. [28]Batut PJ Genome organization controls transcriptional dynamics during development. Science 375, 566– 570, doi: 10.1126/science.abi7178 (2022). 35113722 PMC10368186 · DOI
  25. [29]Judd J, Duarte FM & Lis JT Pioneer-like factor GAF cooperates with PBAP (SWI/SNF) and NURF (ISWI) to regulate transcription. Genes & Development 35, 147– 156, doi: 10.1101/gad.341768.120 (2021). 33303640 PMC7778264 · DOI
  26. [30]Tsai A. Nuclear microenvironments modulate transcription from low-affinity enhancers. Elife 6, doi: 10.7554/eLife.28975 (2017). PMC5695909 29095143 · DOI
  27. [31]Mir M. Dynamic multifactor hubs interact transiently with sites of active transcription in Drosophila embryos. Elife 7, doi: 10.7554/eLife.40497 (2018). PMC6307861 30589412 · DOI · Paper page
  28. [32]Tsai A, Alves MR & Crocker J. Multi-enhancer transcriptional hubs confer phenotypic robustness. Elife 8, doi: 10.7554/eLife.45325 (2019). PMC6650246 31294690 · DOI
  29. [33]Li J. Single-gene imaging links genome topology, promoter-enhancer communication and transcription control. Nat Struct Mol Biol 27, 1032– 1040, doi: 10.1038/s41594-020-0493-6 (2020). 32958948 PMC7644657 · DOI
  30. [34]Eagen KP, Aiden EL & Kornberg RD Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map. Proc Natl Acad Sci U S A 114, 8764– 8769, doi: 10.1073/pnas.1701291114 (2017). 28765367 PMC5565414 · DOI
  31. [35]Ogiyama Y, Schuettengruber B, Papadopoulos GL, Chang JM & Cavalli G. Polycomb-Dependent Chromatin Looping Contributes to Gene Silencing during Drosophila Development. Mol Cell 71, 73– 88 e75, doi: 10.1016/j.molcel.2018.05.032 (2018). 30008320 · DOI
  32. [36]Kyrchanova O. The bithorax complex iab-7 Polycomb response element has a novel role in the functioning of the Fab-7 chromatin boundary. PLoS Genet 14, e1007442, doi: 10.1371/journal.pgen.1007442 (2018). PMC6110506 30110328 · DOI
  33. [37]Espinola SM Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during early Drosophila development. Nat Genet 53, 477– 486, doi: 10.1038/s41588-021-00816-z (2021). 33795867 · DOI · Paper page
  34. [38]Ing-Simmons E. Independence of chromatin conformation and gene regulation during Drosophila dorsoventral patterning. Nat Genet 53, 487– 499, doi: 10.1038/s41588-021-00799-x (2021). 33795866 PMC8035076 · DOI · Paper page
  35. [39]Di Giammartino DC KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks. Nature Cell Biology 21, 1179– 1190, doi: 10.1038/s41556-019-0390-6 (2019). 31548608 PMC7339746 · DOI
  36. [40]Fanucchi S, Shibayama Y, Burd S, Marc & Musa. Chromosomal Contact Permits Transcription between Coregulated Genes. Cell 155, 606– 620, doi: 10.1016/j.cell.2013.09.051 (2013). 24243018 · DOI
  37. [41]Spilianakis CG & Flavell RA Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nature Immunology 5, 1017– 1027, doi: 10.1038/ni1115 (2004). 15378057 · DOI
  38. [42]Allahyar A. Enhancer hubs and loop collisions identified from single-allele topologies. Nature Genetics 50, 1151– 1160, doi: 10.1038/s41588-018-0161-5 (2018). 29988121 · DOI · Paper page
  39. [43]Montavon T. A regulatory archipelago controls Hox genes transcription in digits. Cell 147, 1132– 1145, doi: 10.1016/j.cell.2011.10.023 (2011). 22118467 · DOI · Paper page
  40. [44]Alliance of Genome Resources, C. Alliance of Genome Resources Portal: unified model organism research platform. Nucleic Acids Res 48, D650– D658, doi: 10.1093/nar/gkz813 (2020). 31552413 PMC6943066 · DOI
  41. [45]Dao LTM Genome-wide characterization of mammalian promoters with distal enhancer functions. Nat Genet 49, 1073– 1081, doi: 10.1038/ng.3884 (2017). 28581502 · DOI · Paper page
  42. [46]Diao Y. A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods 14, 629– 635, doi: 10.1038/nmeth.4264 (2017). 28417999 PMC5490986 · DOI · Paper page
  43. [47]Pachano T. Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness. Nat Genet 53, 1036– 1049, doi: 10.1038/s41588-021-00888-x (2021). 34183853 PMC7611182 · DOI · Paper page
  44. [48]Schroeder MD, Greer C. & Gaul U. How to make stripes: deciphering the transition from non-periodic to periodic patterns in Drosophila segmentation. Development 138, 3067– 3078, doi: 10.1242/dev.062141 (2011). 21693522 PMC3119311 · DOI
  45. [49]Kvon EZ Genome-scale functional characterization of Drosophila developmental enhancers in vivo. Nature 512, 91– 95, doi: 10.1038/nature13395 (2014). 24896182 · DOI
  46. [50]Wieschaus E. & Nusslein-Volhard C. The Heidelberg Screen for Pattern Mutants of Drosophila: A Personal Account. Annu Rev Cell Dev Biol 32, 1– 46, doi: 10.1146/annurev-cellbio-113015-023138 (2016). 27501451 · DOI
  47. [51]Lim B, Heist T, Levine M. & Fukaya T. Visualization of Transvection in Living Drosophila Embryos. Molecular Cell 70, 287– 296.e286, doi: 10.1016/j.molcel.2018.02.029 (2018). 29606591 PMC6092965 · DOI
  48. [52]Rogers WA, Goyal Y, Yamaya K, Shvartsman SY & Levine MS Uncoupling neurogenic gene networks in the Drosophila embryo. Genes Dev 31, 634– 638, doi: 10.1101/gad.297150.117 (2017). 28428262 PMC5411704 · DOI
  49. [53]Ren X. Optimized gene editing technology for Drosophila melanogaster using germ line-specific Cas9. Proc Natl Acad Sci U S A 110, 19012– 19017, doi: 10.1073/pnas.1318481110 (2013). 24191015 PMC3839733 · DOI
  50. [54]Dubuis JO, Samanta R. & Gregor T. Accurate measurements of dynamics and reproducibility in small genetic networks. Molecular Systems Biology 9, 639, doi: 10.1038/msb.2012.72 (2013). 23340845 PMC3564256 · DOI
  51. [56]Li H. & Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754– 1760, doi: 10.1093/bioinformatics/btp324 (2009). 19451168 PMC2705234 · DOI · Paper page
  52. [57]Abdennur N. & Mirny LA Cooler: scalable storage for Hi-C data and other genomically labeled arrays. Bioinformatics 36, 311– 316, doi: 10.1093/bioinformatics/btz540 (2020). 31290943 PMC8205516 · DOI · Paper page
  53. [58]Kerpedjiev P. HiGlass: web-based visual exploration and analysis of genome interaction maps. Genome Biol 19, 125, doi: 10.1186/s13059-018-1486-1 (2018). 30143029 PMC6109259 · DOI
  54. [59]Kruse K, Hug CB & Vaquerizas JM FAN-C: a feature-rich framework for the analysis and visualisation of chromosome conformation capture data. Genome Biol 21, 303, doi: 10.1186/s13059-020-02215-9 (2020). 33334380 PMC7745377 · DOI
  55. [60]Wood AM Regulation of chromatin organization and inducible gene expression by a Drosophila insulator. Mol Cell 44, 29– 38, doi: 10.1016/j.molcel.2011.07.035 (2011). 21981916 PMC3190163 · DOI
  56. [61]Larkin A. FlyBase: updates to the Drosophila melanogaster knowledge base. Nucleic Acids Res 49, D899– D907, doi: 10.1093/nar/gkaa1026 (2021). 33219682 PMC7779046 · DOI
  57. [62]Bothma JP Enhancer additivity and non-additivity are determined by enhancer strength in the Drosophila embryo. eLife 4, doi: 10.7554/elife.07956 (2015). PMC4532966 26267217 · DOI · Paper page

Cited by

Sorted by citations

Authors
Levo, M., Raimundo, J., Bing, X. Y., Sisco, Z., Batut, P. J., Ryabichko, S., Gregor, T., & Levine, M. S.
Affiliations
  • Princeton University (US)
  • Institut Pasteur (FR)
Corresponding author
  • Gregor, Thomas
  • Levine, Michael S.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-05-04
Volume
605
Issue
7911
Pages
754-760
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04680-7
PMC
PMC9886134
OpenAlex
W4229004838
Cited by
188
References
6
Citations by year
2026: 35 · 2025: 50 · 2024: 41 · 2023: 44 · 2022: 17 · 2021: 1
FWCI
12.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-19-CE45-0016)
  • National Institute on Drug Abuse (U01DA047730)
  • National Institute of General Medical Sciences (R01GM097275, R35GM118147)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK127429)
  • National Institute of Biomedical Imaging and Bioengineering (U01EB021239)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
long-range gene regulation, Drosophila embryo, paralogs, transcriptional bursting, genome topology, single-cell live imaging
MeSH terms
Animals, Drosophila, Enhancer Elements, Genetic, Genes, Regulator, Promoter Regions, Genetic, Transcription, Genetic, Genome, Gene Expression Regulation, Developmental, Embryonic Development, Single-Cell Analysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review