How chromosome topologies get their shape: views from proximity ligation and microscopy methods

TY - JOUR

T1 - How chromosome topologies get their shape

T2 - views from proximity ligation and microscopy methods

AU - Huang, Yike

AU - Neijts, Roel

AU - de Laat, Wouter

N1 - © 2020 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2020/11

Y1 - 2020/11

N2 - The 3D organization of our genome is an important determinant for the transcriptional output of a gene in (patho)physiological contexts. The spatial organization of linear chromosomes within nucleus is dominantly inferred using two distinct approaches, chromosome conformation capture (3C) and DNA fluorescent in situ hybridization (DNA-FISH). While 3C and its derivatives score genomic interaction frequencies based on proximity ligation events, DNA-FISH methods measure physical distances between genomic loci. Despite these approaches probe different characteristics of chromosomal topologies, they provide a coherent picture of how chromosomes are organized in higher-order structures encompassing chromosome territories, compartments, and topologically associating domains. Yet, at the finer topological level of promoter-enhancer communication, the imaging-centered and the 3C methods give more divergent and sometimes seemingly paradoxical results. Here, we compare and contrast observations made applying visual DNA-FISH and molecular 3C approaches. We emphasize that the 3C approach, due to its inherently competitive ligation step, measures only 'relative' proximities. A 3C interaction enriched between loci, therefore does not necessarily translates into a decrease in absolute spatial distance. Hence, we advocate caution when modeling chromosome conformations.

AB - The 3D organization of our genome is an important determinant for the transcriptional output of a gene in (patho)physiological contexts. The spatial organization of linear chromosomes within nucleus is dominantly inferred using two distinct approaches, chromosome conformation capture (3C) and DNA fluorescent in situ hybridization (DNA-FISH). While 3C and its derivatives score genomic interaction frequencies based on proximity ligation events, DNA-FISH methods measure physical distances between genomic loci. Despite these approaches probe different characteristics of chromosomal topologies, they provide a coherent picture of how chromosomes are organized in higher-order structures encompassing chromosome territories, compartments, and topologically associating domains. Yet, at the finer topological level of promoter-enhancer communication, the imaging-centered and the 3C methods give more divergent and sometimes seemingly paradoxical results. Here, we compare and contrast observations made applying visual DNA-FISH and molecular 3C approaches. We emphasize that the 3C approach, due to its inherently competitive ligation step, measures only 'relative' proximities. A 3C interaction enriched between loci, therefore does not necessarily translates into a decrease in absolute spatial distance. Hence, we advocate caution when modeling chromosome conformations.

U2 - 10.1002/1873-3468.13961

DO - 10.1002/1873-3468.13961

M3 - Book/Film/Article review

C2 - 33073863

SN - 0014-5793

VL - 594

SP - 3439

EP - 3449

JO - FEBS Letters

JF - FEBS Letters

IS - 21

ER -