Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Nucleus. 2019 Dec;10(1):7-20. doi: 10.1080/19491034.2019.1570810.

Abstract

Immunosuppressive drugs such as cyclosporin A (CsA) can elicit hepatotoxicity by affecting gene expression. Here, we address the link between CsA and large-scale chromatin organization in HepG2 hepatocarcinoma cells. We show the existence of lamina-associated domains (LADs) interacting with lamin A, lamin B, or both. These 'A-B', 'A-only' and 'B-only' LADs display distinct fates after CsA treatment: A-B LADs remain constitutive or lose A, A-only LADs mainly lose A or switch to B, and B-only LADs remain B-only or acquire A. LAD rearrangement is overall uncoupled from changes in gene expression. Three-dimensional (3D) genome modeling predicts changes in radial positioning of LADs as LADs switch identities, which are corroborated by fluorescence in situ hybridization. Our results reveal interplay between A- and B-type lamins on radial locus positioning, suggesting complementary contributions to large-scale genome architecture. The data also unveil a hitherto unsuspected impact of cytotoxic drugs on genome conformation.Abbreviations: ChIP-seq: chromatin immunoprecipitation sequencing; CsA: cyclosporin A; FISH; fluorescence in situ hybridization; ICMT: isoprenylcysteine methyltransferase; LAD: lamina-associated domain; TAD: topologically-associated domain.

Keywords: 3D genome; Chromatin; LAD; genome conformation; nuclear lamins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / drug effects
  • Chromatin / metabolism*
  • Cyclosporine / pharmacology
  • Hep G2 Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lamin Type A / antagonists & inhibitors
  • Lamin Type A / metabolism*
  • Lamin Type B / antagonists & inhibitors
  • Lamin Type B / metabolism*
  • Models, Genetic
  • Nuclear Lamina / drug effects
  • Nuclear Lamina / metabolism*
  • Tumor Cells, Cultured

Substances

  • Chromatin
  • Lamin Type A
  • Lamin Type B
  • Cyclosporine

Grant support

This work is funded by the Research Council of Norway, South East Health Norway, and EU Scientia Fellowship FP7-PEOPLE-2013-COFUND No. 609020 (A.B.).