Genomic profiling of HIV-1 integration in microglia cells links viral integration to the topologically associated domains
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223638 | GEO | 2023/01/24
REPOSITORIES: GEO
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Project description:HIV-1 integration introduces ectopic transcription factor binding sites into host chromatin. We postulate that the integrated provirus serves as an ectopic enhancer that recruits additional transcriptional factors to the integration locus, increases chromatin accessibility, changes 3D chromatin interactions, and enhances both retroviral and host gene expression. We used 4 well-characterized HIV-1-infected cell line clones having unique integration sites and low to high levels of HIV-1 expression. Using single-cell DOGMA-seq, which captured the heterogeneity of HIV-1 expression and host chromatin accessibility, we found that HIV-1 transcription correlated with HIV-1 accessibility and host chromatin accessibility. HIV-1 integration increased local host chromatin accessibility within ~5–30 kb distance. CRISPRa and CRISPRi-mediated HIV-1 promoter activation and inhibition confirmed integration site-dependent HIV-1-driven changes of host chromatin accessibility. HIV-1 did not drive chromatin confirmation changes at the genomic level (by Hi-C) or the enhancer connectome (by H3K27Ac HiChIP). Using 4C-seq to interrogate HIV-1-chromatin interactions, we found that HIV-1 interacted with host chromatin ~100–300 kb from the integration site. By identifying chromatin regions having both increased transcription factor activity (by ATAC-seq) and HIV-1-chromtain interaction (by 4C-seq), we identified enrichment of ETS, RUNT, STAT, and ZNF transcription factor binding that may mediate HIV-1-host chromatin interactions. Our study found that HIV-1 promoter activity increased host chromatin accessibility, increased HIV-1-host chromatin interactions in an integration site dependent manner, within the existing chromatin boundaries without impacting broader host chromatin structure.
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Project description:HIV-1 integration introduces ectopic transcription factor binding sites into host chromatin. We postulate that the integrated provirus serves as an ectopic enhancer that recruits additional transcriptional factors to the integration locus, increases chromatin accessibility, changes 3D chromatin interactions, and enhances both retroviral and host gene expression. We used 4 well-characterized HIV-1-infected cell line clones having unique integration sites and low to high levels of HIV-1 expression. Using single-cell DOGMA-seq, which captured the heterogeneity of HIV-1 expression and host chromatin accessibility, we found that HIV-1 transcription correlated with HIV-1 accessibility and host chromatin accessibility. HIV-1 integration increased local host chromatin accessibility within ~5–30 kb distance. CRISPRa and CRISPRi-mediated HIV-1 promoter activation and inhibition confirmed integration site-dependent HIV-1-driven changes of host chromatin accessibility. HIV-1 did not drive chromatin confirmation changes at the genomic level (by Hi-C) or the enhancer connectome (by H3K27Ac HiChIP). Using 4C-seq to interrogate HIV-1-chromatin interactions, we found that HIV-1 interacted with host chromatin ~100–300 kb from the integration site. By identifying chromatin regions having both increased transcription factor activity (by ATAC-seq) and HIV-1-chromtain interaction (by 4C-seq), we identified enrichment of ETS, RUNT, STAT, and ZNF transcription factor binding that may mediate HIV-1-host chromatin interactions. Our study found that HIV-1 promoter activity increased host chromatin accessibility, increased HIV-1-host chromatin interactions in an integration site dependent manner, within the existing chromatin boundaries without impacting broader host chromatin structure.
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Project description:We performed LM-PCR in an infected microglia cell line (C20) to map HIV-1 integration sites. Our aim was to compare the IS obtained through this method with ChIP-seq, ATAC-seq, and RNA-seq data obtained in the uninfected cells, allowing the assessment of integration preferences.
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Project description:The three-dimensional structure of the genome is a regulator of transcription and cell function; HIV-1 infection can influence host cell function, but the degree to which this is mediated through changes to host chromatin architecture is unclear. We interrogated genome-wide chromatin organization and the structure of chromatin around latently infected HIV-1 integration sites using Hi-C and ATAC-seq and combined these data with RNA transcriptional analysis of the provirus and neighboring genes in HIV-inducible cellular models. We found chromatin interaction networks around integrated HIV-1 are predominantly preserved with respect to uninfected cells, proving the lack of an obligate association between latent integration and major chromatin remodeling. Instead, we find that induction of proviral transcription may lead to local changes in chromatin accessibility downstream from the 3’ LTR, demonstrating that HIV-1 can alter local cellular chromatin structure post-integration. Using long-read Nanopore RNA-seq, we interrogated the local host and HIV-1 transcriptomes and observed that 1-5% of HIV-1 transcripts initiated at the 5’ LTR promoter extended into the flanking cellular genome, generating chimeric virus-host RNAs. Thus, integration leading to latency (and provirus activation) may not lead to obligate global chromatin rearrangements; we also observed, previously unreported, novel changes in chromatin accessibility during HIV-1 transcription.
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