Abstract
ABSTRACTImmunosuppressive 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
Highlights
Drug-induced hepatotoxicity, a common cause of clinical trial failure, has led to the use of cellular models such as HepG2 hepatocarcinoma cells for drug testing [1,2]
Before investigating changes in genome organization that might be elicited by cyclosporin A (CsA), we determined whether CsA altered levels of nuclear lamins
We report a marked effect of CsA on the association of chromatin with A- and/or B-type lamins
Summary
Drug-induced hepatotoxicity, a common cause of clinical trial failure, has led to the use of cellular models such as HepG2 hepatocarcinoma cells for drug testing [1,2]. The mammalian genome is organized into compartments of active and inactive chromatin [5] and within these, regions of high-frequency chromosomal interactions termed topologically associated domains (TADs) [6,7]. The genome is radially organized, with lamina-associated domains (LADs) anchoring chromatin to the nuclear lamina, at the nuclear periphery [8], a meshwork of lamins A/C (from here on, ‘lamin A’) and B [9]. A minor fraction of lamin B1 has been found in the nuclear interior in association with euchromatin [17] These observations suggest that alterations in lamin-genome interactions may impact genome organization at the nuclear periphery and in the nuclear interior
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
