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Nuclear lamina binds the EBV genome during latency and regulates viral gene expression [Hi-C]

ABSTRACT: Approximately 90% of the world population is infected with EBV and carries the virus in a silent, asymptomatic state for life. In immunocompromised individuals, EBV infection can cause B-cell transformation and malignancies. One approach to control EBV infectivity is by changing the expression of viral genes. We are interested in how epigenetics contributes to regulating the gene expression patterns adopted by EBV during latency. The host’s hijacking is a well know strategy adopted by viruses to modify the epigenome, the transcriptome and the proteome of the host with the aim to survive and remain silent in the host. We observed that in B cells, EBV infection mimics antigen-mediated activation, resulting in the induction of specific proteins named Lamin A/C. Lamins have multiple and central roles: they provide nuclear physical support, anchor the heterochromatin to the nuclear periphery and seem to play a role in several nuclear functions requiring the chromatin structure rearrangement. The interaction with lamins has already been studied in the context of EBV lytic reactivation, but their role in the control of the EBV latency states and as epigenetic regulators of different EBV genes expression profiles has not been investigated. The binding of the Lamin AC to important regulatory regions of EBV genome was assessed through ChIP-Seq, and gene expression (RNA-Seq) profiles were evaluated in wild type and Lamin AC KO cell lines. Differences in protein and RNA expressions in B cells activated by using both EBV and a simulation of the immune response were analyzed. Our data suggest two main conclusions: lamins might contribute to the epigenetic control of EBV genes expression during latency changing the interaction of the host structural proteins with key regulatory regions in the viral genome and a possible mechanism with who EBV modifies the nucleus and hijacks cellular mechanisms.

ORGANISM(S): human gammaherpesvirus 4 Homo sapiens

PROVIDER: GSE198412 | GEO | 2022/04/08

REPOSITORIES: GEO

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Project description:Purpose: to qualify and quantify the rearrangement of interactions of nuclear lamins A/C and B with the genome, in relation to nuclearradial repositioning of loci and changes in gene expression, in HepG2 cells exposed to cyclosporin A. .To compare HepG2 cell line transcriptome profiling (RNA-seq) with radially positioning of the chromatin anchored at the nuclear periphery before and after CsA treatment. Methods: To this end, we mapped lamin A and lamin B lamina-associated domains (LADs) by chromatin immunoprecipitation-sequencing (ChIP-seq) of lamin A/C (antibody sc7292x, Santa Cruz Biotechnology) and lamin B1 (antibody ab16048, Abcam), respectively. HepG2 cells were either cultured under proliferative conditions (controls) or exposed for 3 days to 10 uM cyclosporin A. We also assesed the transcriptome by RNA-seq under each condition in duplicate cultures. Results: CsA elicits accumulation of pre-lamin A in HepG2 cells, raising the hypothesis of a global rearrangement of lamin-chromatin interactions. We show here the existence of overlapping and distinct lamin A and B lamina-associated domains (which we refer to as A- and B-LADs, respectively). Whereas B-LADs largely remain constitutive, CsA elicits the formation of facultative A-LADs. Re-localization of A-LADs occur mainly on preexisting B-LADs. However, LAD rearrangement does not correlate with systematic changes in gene expression within LADs. We find a reorganization of A- and B-LADs after CsA treatment, entailing distinct contributions of A- and B- type lamins. to genome organization. Indeed, classification of lamin A LADs and lamin B LADs into properties of ‘A-only’, ‘B-only’ and ‘A-B’ LADs show an overall loss of A-only LADs after CsA treatment. A- only and B-only LADs are highly dynamic with A-B LADs being more stable.The rearrangement of lamin association after CsA treatment correlates with repositioning of loci in the nuclear space with, notably, a loss of lamin B associated with a re-localization of loci towards the nuclear center and conversely, a gain of lamin B linked to a repositioning of loci towards the nuclear periphery. Predictions on radial repositioning of LADs, and of loci within, from 3D structural models of the genome were supported by fluorescence in situ hybridization (FISH) analyses. Conclusions: We show that, while they amply co-localize on well-conserved LADs, lamins A and B also interact with distinct genomic regions that can interchange (switch) between lamin A and B upon CsA treatment. We unveil distinct lamin A and B interactions with chromatin, suggesting complementary contributions to genome conformation. Our data suggest that and lamins A and B may differentially modulate genome organization.

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Nuclear lamina binds the EBV genome during latency and regulates viral gene expression [Hi-C]

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