Integration Site-dependent HIV-1 Promoter Activity Shapes Host Chromatin Conformation

Overview

Journal Genome Res

Specialty Genetics

Date 2023 Jun 9

PMID 37295842

Authors

Jack A Collora

Ya-Chi Ho

Affiliations

Soon will be listed here.

Abstract

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 transcription factors to the integration locus, increases chromatin accessibility, changes 3D chromatin interactions, and enhances both retroviral and host gene expression. We used four 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 an ∼5- to 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-chromatin interaction (by 4C-seq), we identified enrichment of ETS, RUNT, and ZNF-family transcription factor binding that may mediate HIV-1-host chromatin interactions. Our study has found that HIV-1 promoter activity increases host chromatin accessibility, and HIV-1 interacted with host chromatin within the existing chromatin boundaries in an integration site-dependent manner.

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