Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of LANA induction in human Burkitts lymphoma cell line, KSHV latent infection in lymphoma and endothelial cell lines

ABSTRACT: Gene expression profiling of three PEL cell lines compare to three Burkitt's lymphoma lines to figure out the changed genes under KSHV latent infection. Gene expression profiling of two time points on TIVE cells after infection by KSHV compare to TIVE cell without infection by KSHV to figure out the changed genes on TIVE cell under latent infection of KSHV. Gene expression profiling of four time points after inducing recombinant LANA protein expression when compare to no inducing BJAB/Tet-On/LANA cells to figure out the changed genes under the latency-associate nuclear antigen (LANA) of KSHV expression. Gene expression profiling of three time points after inducing recombinant LANA protein expression when compare to no inducing Jurkat/Tet-On/LANA cell line to figure out the changed genes under the latency-associate nuclear antigen (LANA) of KSHV expression. Gene expression profiling of two time points after inducing recombinant LANA protein expression when compare to no inducing 293/Tet-On/LANA cell line to figure out the changed genes under the latency-associate nuclear antigen (LANA) of KSHV expression.

ORGANISM(S): Homo sapiens

DISEASE(S): acute lymphocytic leukemia

SUBMITTER: Feng-Qi An

PROVIDER: E-GEOD-1880 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest.

An Feng-Qi FQ Compitello Nicole N Horwitz Edward E Sramkoski Michael M Knudsen Erik S ES Renne Rolf R

The Journal of biological chemistry 20041102 5

Latently infected Kaposi's sarcoma-associated herpes-virus (KSHV)-associated tumor cells have both endothelial and lymphoid origins and express a limited set of latent viral genes. One such gene, ORF73, encodes the latency-associated nuclear antigen (LANA), a multifunctional protein that plays roles in viral DNA replication, episome maintenance, and transcriptional regulation. LANA interacts with cellular proteins involved in transcriptional regulation such as the tumor suppressors, retinoblasto ...[more]

PMID: 15525642

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Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is a g-herpesvirus which persists as circular extrachromasomal DNA in the nucleus during latent infection. During latency a limited number of viral proteins are expressed, including LANA (latency-associated nuclear antigen). LANA is a multi-functional protein known to interact with transcriptional regulators and chromatin remodelers, and to regulate the LANA and RTA promoters. We hypothesized that LANA may contribute to the establishment of latency through controlling chromatinization and histone modification of KSHV episomes. We performed ChIP-seq analysis and correlated H3K4me3, H3K27me3, polII, and LANA occupancy of the KSHV genome at nucleotide resolution. Epigenetic marks were analyzed in BCBL-1 lymphoid cells and in telomerase-immortalized vein endothelial TIVE-LTC cells. We found that the transcription active mark H3K4me3, but not silencing mark H3K27me3, was enriched at KSHV regions where LANA is bound. Co-occupancy of LANA and H3K4 was also detected on 167 host genes, of which 89 are actively transcribed. By comparing LANA occupancy with the profiling of 43 transcription factors from ENCODE, a subset of transcription factors was enriched at regions where LANA is bound, including znf143, CTCF, and Stat1. These results indicate that LANA also plays a role in modulating expression of host genes. Co-immunoprecipitation of LANA with the H3K4 methyltransferase hSET1 suggests that LANA recruits hSET1 to specific loci on the viral genome, leading to H3K4 methylation and ensuring transcription of latency-associated genes. Host gene expression may be regulated by the same mechanism. LANA binding was correlated with the distribution in the latent KSHV genome of the transcription active histone modification H3K4me3, the silencing mark H3K27me3, and RNA polymerase II, using cells of lymphoid and endothelial origin. A similar analysis was done for the human genome. Biological replicates (BR) and technical replicates (TR) were included.

Project description:The Kaposi's sarcoma-associated herpesvirus (KSHV) genome consists of an approximately 140 kb unique coding region flanked by 30-40 copies of 0.8 kb terminal repeat (TR) sequence. KSHV genomes persist in latently infected cells as episomes via tethering to the host cell chromosomes, and KSHV latency associated nuclear antigen (LANA) plays a crucial role in latent episomal DNA replication and segregation during host cell mitosis by binding to TR. While TR's function in plasmid maintenance is well-established, TR’s transcription regulatory roles as gene enhancer has not been fully explored. Gene enhancer harbors transcription enzymes via arrays of transcription factors bindings and often forms phase separate nuclear body in part through recruitment of BRD4 and MED1 that contain intrinsically disordered domain. Here we show KSHV TR possesses transcription regulatory function with LANA. A series of Cleavage Under Targets & Release Using Nuclease (CUT&RUN) demonstrated that TR fragments are occupied by histone modifying enzymes that are known to interact with LANA in naturally infected cells, and the TR possessed characteristic enhancer histone modifications. The H3K4me3 and H3K27Ac modification were also conserved in unique region of the KSHV genome among three PEL cells, and the KSHV Origin of lytic replication (Ori-Lyt) showed similar protein and histone modification occupancies with TR's. In the Ori-Lyt region, the LANA protein complex colocalizes with H3K27Ac-modified nucleosome along with paused RNA polymerase II, and the nucleosome is franked by two K-Rta recruitment sites. The isolated reporter assays demonstrated that neighboring TR fragments enhanced viral lytic gene promoter activity independent of orientation in KSHV-infected and non-infected 293FT cells. K-Rta transactivation function was drastically enhanced with TR, while LANA acquired promoter repression function when the reporter was ligated with TR. The deletion of LANA acidic repeat sequence, a highly-disordered protein domain, further increased gene repression functions. Combined, the TR region is (i) an epigenetically active DNA element that is stitched within 12.5 kb (20-40 copies), (ii) has an array of transcription factor (LANA) binding sites, (iii) recruited by transcription related enzymes including BRD4 (bromodomain containing 4), (iv) decorated by histone H3K27Ac marks, and (v) possesses orientation-independent transcription activation function. KSHV TR is therefore an enhancer domain for KSHV inducible genes. However, in contrast to cellular enhancers that are bound by multiple transcription factors, perhaps KSHV enhancer is predominantly regulated by the LANA nuclear body on the TR. We suggest that KSHV evolved a clever mechanism to tightly control the latency-lytic switch with the TR/LANA complex.

Dataset Information

Transcription profiling of LANA induction in human Burkitts lymphoma cell line, KSHV latent infection in lymphoma and endothelial cell lines

Publications

The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest.

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