Cited by 376Genomics and Chromatin DynamicsChromosomal and Genetic VariationsChromatin Remodeling and Cancer

Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression

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Ghavi-Helm, Yad, Jankowski, Aleksander, Meiers, Sascha, Viales, Rebecca R., Korbel, Jan O., Furlong, Eileen E. M.·2019·Nature Genetics

Abstract

Chromatin topology is intricately linked to gene expression, yet its functional requirement remains unclear. Here, we comprehensively assessed the interplay between genome topology and gene expression using highly rearranged chromosomes (balancers) spanning ~75% of the Drosophila genome. Using transheterozyte (balancer/wild-type) embryos, we measured allele-specific changes in topology and gene expression in cis, while minimizing trans effects. Through genome sequencing, we resolved eight large nested inversions, smaller inversions, duplications and thousands of deletions. These extensive rearrangements caused many changes to chromatin topology, disrupting long-range loops, topologically associating domains (TADs) and promoter interactions, yet these are not predictive of changes in expression. Gene expression is generally not altered around inversion breakpoints, indicating that mis-appropriate enhancer-promoter activation is a rare event. Similarly, shuffling or fusing TADs, changing intra-TAD connections and disrupting long-range inter-TAD loops does not alter expression for the majority of genes. Our results suggest that properties other than chromatin topology ensure productive enhancer-promoter interactions.

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  • Considerable TAD re-arrangements observed in Drosophila balancer chromosomes compared with wild-type result in changes in expression of only about 10% of genes.

    “the considerable TAD re-arrangements observed in Drosophila balancer chromosomes compared with their wild-type counterparts result in changes in the expression of only ~ 10% of genes [449].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [449]

    The Results section reports that 512 of 5,357 testable genes (9.6%) differed in expression between balancer and wild-type haplotypes. But that figure covers the chromosomes’ extensive genomic rearrangements overall, not changes caused specifically by TAD rearrangements. The TAD analysis reports differential expression for 23 of 161 expressed genes in resized TADs and 29 of 237 testable genes near perturbed boundaries. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • Biochemical annotations fail to specify which gene(s) a putative enhancer regulates, let alone the degree of activation conferred.

    “Third, biochemical annotations fail to specify which gene(s) a putative enhancer regulates, let alone the degree of activation conferred78,79.”

    From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [78]

    The Abstract and Discussion report that changes in chromatin topology do not reliably predict gene-expression changes. The Online Methods describe using DNase hypersensitivity and enhancer annotations, but our copy does not assess whether biochemical annotations identify an enhancer’s target genes or quantify the activation it confers. Searches for those specific points found no deciding passage; page numbers were unavailable in our copy. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 2

  1. [58]Ramírez F High-resolution TADs reveal DNA sequences underlying genome organization in flies Nat Commun 2018 9 189 29335486 PMC5768762
  2. [62]Thomas S Dynamic reprogramming of chromatin accessibility during Drosophila embryo development Genome Biol 2011 12 R43 21569360 PMC3219966

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Authors
Ghavi-Helm, Y., Jankowski, A., Meiers, S., Viales, R. R., Korbel, J. O., & Furlong, E. E. M.
Affiliations
  • Lyon 1 Université (FR)
  • European Molecular Biology Laboratory (DE)
Corresponding author
  • Ghavi-Helm, Yad
  • Korbel, Jan O.
  • Furlong, Eileen E. M.
Venue
Nature Genetics
Published
2019-07-15
Volume
51
Issue
8
Pages
1272-1282
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2958578938
Cited by
354
References
57
Citations by year
2026: 16 · 2025: 33 · 2024: 41 · 2023: 54 · 2022: 60 · 2021: 74 · 2020: 56 · 2019: 19
FWCI
17.94
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
Nature
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
chromatin topology, gene expression, balancer chromosomes, chromosomal inversions, topologically associating domains, enhancer-promoter interactions, cis effect, Drosophila, chromosomal duplication, chromosomal deletion
MeSH terms
Animals, Chromatin, Chromosome Mapping, Drosophila melanogaster, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Male, Promoter Regions, Genetic, Gene Rearrangement, Genome, Insect, Chromosomes, Insect

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