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Cell. 2014 Jul 17;158(2):339-352. doi: 10.1016/j.cell.2014.05.036. Epub 2014 Jul 3.

3D trajectories adopted by coding and regulatory DNA elements: first-passage times for genomic interactions.

Author information

1
Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Physics and Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Physics and Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dudko@physics.ucsd.edu.
4
Division of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: murre@biomail.ucsd.edu.

Abstract

During B lymphocyte development, immunoglobulin heavy-chain variable (VH), diversity (DH), and joining (JH) segments assemble to generate a diverse antigen receptor repertoire. Here, we have marked the distal VH and DH-JH-Eμ regions with Tet-operator binding sites and traced their 3D trajectories in pro-B cells transduced with a retrovirus encoding Tet-repressor-EGFP. We found that these elements displayed fractional Langevin motion (fLm) due to the viscoelastic hindrance from the surrounding network of proteins and chromatin fibers. Using fractional Langevin dynamics modeling, we found that, with high probability, DHJH elements reach a VH element within minutes. Spatial confinement emerged as the dominant parameter that determined the frequency of such encounters. We propose that the viscoelastic nature of the nuclear environment causes coding elements and regulatory elements to bounce back and forth in a spring-like fashion until specific genomic interactions are established and that spatial confinement of topological domains largely controls first-passage times for genomic interactions.

PMID:
24998931
PMCID:
PMC4113018
DOI:
10.1016/j.cell.2014.05.036
[Indexed for MEDLINE]
Free PMC Article

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